Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

ABSTRACT

The invention provides novel compounds having the general formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , M and X are as described herein, compositions including the compounds and methods of using the compounds.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §119(a)to PCT/CN2012/073388 filed Mar. 31, 2012 the contents of which is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a human, and in particular to Hepatitis B virus(HBV) inhibitors by targeting on HBV capsid useful for treating HBVinfection.

HBV is a species of the hepadnaviridae family of viruses. HBV is aserious public health problem worldwide, with more than 400 millionpeople especially in Asia-pacific regions chronically infected by thissmall enveloped DNA virus. Although most individuals seem to resolve theinfection following acute symptoms, 15-40% of HBV patients will finallydevelop clinical diseases during their lifespan, most notably,hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year500,000 to 1 million people die from the end stage of liver diseasescaused by HBV infection.

HBV lifecycle begins with the binding of the “Dane” particle with anunidentified receptor on the surface of hepatocyte. Following entry,viral genome is delivered into nucleus where a covalently closedcircular DNA (cccDNA) is formed through DNA repair of viral relaxedcircular DNA. Unlike the mechanisms of most other DNA viruses, HBVcccDNA replicates through the retrotranscription of a 1.1-genomeunit-length RNA copy (pregenomic RNA). Viral pregenomic RNA interactswith other two viral components, capsid protein and polymerase, as wellas some host factors, to form capsid particles where viral DNAreplication occurs. Most copies of the encapsidated genome thenefficiently associate with the envelope proteins for virion assembly andsecretion; a minority of these genomes are shunted to the nucleus, wherethey are converted to cccDNA.

Currently, there are two types of anti-HBV agents on the market,nucleoside (tide) analogs targeting viral polymerase (lamivudine,adefovir, tenofovir, telbivudine and entecavir) and interferonmodulating host immune functions. Mutations in the primary sequence ofthe polymerase that confer resistance to lamivudine and adefovir havebeen identified clinically and underlie a rebound of serum virus titersthat 70% of treated patients experience within 3 years of the start oflamivudine therapy. Although resistance to telbivudine, adefovir, andentecavir occurs more rarely, it has been recorded. Interferon alpha isthe other major therapy available for hepatitis B, but it is limited bya poor long-term response and debilitating side effects. Some viralgenotypes do not show good responses to interferon therapy. Now, thestandard of clinic cure of HBV infection is the loss and/orseroconversion of HBsAg. The majority (around or more than 90%) oftreated patients fail to achieve this goal. This drawback is mainly dueto the presence of a stable pool of viral cccDNA in nucleus that doesn'treplicate itself, therefore, shows no accessibility to nucleoside (tide)analogs.

Hence, there is certainly a medical need for treatments with improvedcharacteristics, and for a diversity of approaches in the development oftherapies for HBV infection.

HBV capsid protein plays essential roles in HBV replication. HBV has anicosahedral core comprising of 240 copies of the capsid (or core)protein. The predominant biological function of capsid protein is to actas a structural protein to encapsidate pre-genomic RNA and form immaturecapsid particles in the cytoplasm. This step is prerequisite for viralDNA replication. The HBV capsid spontaneously self-assembles from manycopies of core dimers present in the cytoplasm. It has been shown thatthe formation of a trimeric nucleus and the subsequent elongationreactions occur by adding one dimeric subunit at a time until it iscomplete. Besides this function, capsid protein regulates viral DNAsynthesis through different phosphorylation status of its C-terminalphosphorylation sites. When a near full-length relaxed circular DNA isformed through reverse-transcription of viral pregenomic RNA, animmature capsid becomes a mature capsid. On one hand, capsid proteinmight facilitate the nuclear translocation of viral relaxed circulargenome by means of the nuclear localization signals located in theArginine-rich domain of the C-terminal region of capsid protein. Innucleus, as a component of viral cccDNA minichromosome, capsid proteincould play a structural and regulatory role in the functionality ofcccDNA minichromosomes. Capsid protein also interacts with viral largeenvelope protein in endoplasmic reticulum and triggers the release ofintact viral particles from hepatocytes.

There have been a couple of capsid related anti-HBV inhibitors reported.For example, phenylpropenamide derivatives, including compounds namedAT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177), anda class of thiazolidin-4-ones from Valeant R&D (WO2006/033995), havebeen shown to inhibit pgRNA packaging. A recent study suggested thatphenylpropenamides are, in fact, accelerators of HBV capsid assembly,and their actions result in the formation of empty capsids. These veryinteresting results illustrate the importance of the kinetic pathway insuccessful virus assembly.

Heteroaryldihydropyrimidines or HAP, including compounds named Bay41-4109, Bay 38-7690 and Bay 39-5493, were discovered in a tissueculture-based screening (Deres K. et al. Science 2003, 893). These HAPanalogs act as synthetic allosteric activators and are able to induceaberrant capsid formation that leads to degradation of the core protein.HAP analogs also reorganized core protein from preassembled capsids intononcapsid polymers, presumably by interaction of HAP with dimers freedduring capsid ‘breathing’, the transitory breaking of individualintersubunit bonds. Bay 41-4109 was administered to HBV infectedtransgenic mouse or humanized mouse models and demonstrated in vivoefficacy with HBV DNA reduction (Deres K. et al. Science 2003, 893;Brezillon N. et al. PLoS ONE 2011, e25096.). It was also shown thatbis-ANS, a small molecule that acts as a molecular ‘wedge’ andinterferes with normal capsid-protein geometry and capsid formation(Zlotnick A. et al. J. Virol. 2002, 4848-4854).

SUMMARY OF THE INVENTION

Objects of the present invention are novel compounds of formula I, theirmanufacture, medicaments based on a compound in accordance with theinvention and their production as well as the use of compounds offormula I for the treatment or prophylaxis of HBV infection.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Bay 41-4109 was converted to XLVI in human liver microsomes.

FIG. 2. Mean±SD Plasma Concentration-Time Curve of Bay41-4109 in MaleICR Mice Following Intravenous and Oral Administration* *Drug exposurein liver is not available due to instability of Bay 41-4109 in liverhomogenate.

FIG. 3. Mean±SD Plasma and Tissue Concentration-Time Curve of Example 6in Male ICR Mice Following Intravenous and Oral Administration

FIG. 4. Mean±SD Plasma and Tissue Concentration-Time Curve of Example 11in Male ICR Mice Following Intravenous and Oral Administration

FIG. 5. Mean±SD Plasma and Tissue Concentration-Time Curve of Example 13in Male ICR Mice Following Intravenous and Oral Administration

FIG. 6. Mean±SD Plasma and Tissue Concentration-Time Curve of Example 19in Male ICR Mice Following Intravenous and Oral Administration

FIG. 7. X-ray structure of compound XXVII

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “C₁₋₆alkyl” alone or in combination signifies asaturated, linear- or branched chain alkyl group containing 1 to 6,particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl,isopropyl, 1-butyl, 2-butyl, tert-butyl and the like. Particular“C₁₋₆alkyl” groups are methyl, ethyl, isopropyl, tert-butyl.

The term “cycloalkyl”, alone or in combination, refers to a saturatedcarbon ring containing from 3 to 7 carbon atoms, particularly from 3 to6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like. Particular cycloalkyl groups arecyclopropyl, cyclopentyl and cyclohexyl.

The term “C₁₋₆alkoxy” alone or in combination signifies a groupC₁₋₆alkyl-O—, wherein the “C₁₋₆alkyl” is as defined above; for examplemethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy,t-butoxy and the like. Particular C₁₋₆alkoxy groups are methoxy andethoxy and more particularly methoxy.

The term “C₂₋₆alkoxy” alone or in combination signifies a groupC₂₋₆alkyl-O—, wherein the “C₂₋₆alkyl” alone or in combination signifiesa saturated, linear- or branched chain alkyl group containing 2 to 6,particularly 2 to 4 carbon atoms; for example ethoxy, propoxy,isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy and the like.

The term “C₁₋₂alkoxy” alone or in combination refers to methoxy orethoxy.

The term “C_(y)H_(2y)” alone or in combination signifies a saturated,linear- or branched chain alkyl group containing 1 to 6, particularly 1to 4 carbon atoms.

The term “amino”, alone or in combination, refers to primary (—NH₂),secondary (—NH—) or tertiary amino

The term “carbonyl” alone or in combination refers to the group —C(O)—.

The term “carboxy” alone or in combination refers to the group —COOH.

The term “cyano” alone or in combination refers to the group —CN.

The term “halogen” means fluorine, chlorine, bromine or iodine. Halogenis particularly fluorine or chlorine, more particularly fluorine.

The term “hydroxy” alone or in combination refers to the group —OH.

The term “sulfonyl” alone or in combination refers to the group —S(O)₂—.

The term “morpholinyl” alone or in combination refers to the group (i).When morpholine is formed between either of R⁴ or R⁵ and R⁷ along withthe atoms to which they are attached it represents the group (ii):

The term “pyrrolidinyl” alone or in combination refers to the group(iii). When pyrrolidinyl is formed between either of R⁴ or R⁵ and R⁷along with the atoms to which they are attached it represents the group(iv):

The term “piperidinyl” alone or in combination refers to the group (v).When piperidinyl is formed between either of R⁴ or R⁵ and R⁷ along withthe atoms to which they are attached it represents the group (vi):

The term “tautomers isomers” refers to constitutional isomers of organiccompounds that readily interconvert by a chemical reaction calledtautomerization. This reaction commonly results in the formal migrationof a hydrogen atom or proton, accompanied by a switch of a single bondand adjacent double bond. For example, compounds of general formular (I)

and its tautomers isomer

The term “pharmaceutically acceptable salt” refers to conventionalacid-addition salts or base-addition salts that retain the biologicaleffectiveness and properties of the compounds of formula I and areformed from suitable non-toxic organic or inorganic acids or organic orinorganic bases. Acid-addition salts include for example those derivedfrom inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid andnitric acid, and those derived from organic acids such asp-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalicacid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid,and the like. Base-addition salts include those derived from ammonium,potassium, sodium and, quaternary ammonium hydroxides, such as forexample, tetramethyl ammonium hydroxide. The chemical modification of apharmaceutical compound into a salt is a technique well known topharmaceutical chemists in order to obtain improved physical andchemical stability, hygroscopicity, flowability and solubility ofcompounds. It is for example described in Bastin R. J., et. al., OrganicProcess Research & Development 2000, 4, 427-435; or in Ansel, H., et.al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed.(1995), pp. 196 and 1456-1457. Particular are the sodium salts of thecompounds of formula I.

Compounds of the general formula I which contain one or several chiralcenters can either be present as racemates, diastereomeric mixtures, oroptically active single isomers. The racemates can be separatedaccording to known methods into the enantiomers. Particularly,diastereomeric salts which can be separated by crystallization areformed from the racemic mixtures by reaction with an optically activeacid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid,lactic acid or camphorsulfonic acid.

Inhibitors of Hepatitis B Virus

The present invention provides (i) novel compounds having the generalformula I:

wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl, which is substituted by halogen;

R³ is thiazolyl, thienyl, imidazolyl, isoxazolyl or pyridinyl; which isunsubstituted or substituted by halogen or C₁₋₆alkyl;

X is oxygen or —NR⁷;

R⁴ and R⁵ independently selected from hydrogen, C₁₋₆alkyl andtrifluoroC₁₋₆alkyl; or

R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3 to 7 membered cycloalkyl; or

when X is —NR⁷, one of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the otherof R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ areattached form a pyrrolidinyl, morpholinyl or piperidinyl ring, whichring is unsubstituted or substituted by fluoro;

M is C₁₋₆alkoxycarbonyl, carboxy, diC₁₋₆alkylaminoC₂₋₆alkoxycarbonyl,aminocarbonyl, C₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,C₁₋₆alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,hydroxy-C_(y)H_(2y)—,

R⁷ is C₁₋₆alkyl or trifluoroC₁₋₆alkyl;

y is 1-6;

or pharmaceutically acceptable salts, or tautomerism isomers thereof.

Another embodiment of present invention is (ii) a compound of formula I,wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl, which is once or twice substituted by halogen;

R³ is 2-thiazolyl, which is unsubstituted or once substituted byC₁₋₆alkyl or halogen; or 2-thienyl or 2-pyridinyl, which is oncesubstituted by halogen; or 2-imidazolyl, which is once substituted byC₁₋₆alkyl; or 3-isoxazolyl, which is unsubstituted or once substitutedby C₁₋₆alkyl;

X is oxygen or —NR⁷;

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl andtrifluoroC₁₋₆alkyl; or

R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3 to 7 membered cycloalkyl; or

when X is —NR⁷, one of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the otherof R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ areattached form a morpholinyl; or pyrrolidinyl or piperidinyl, which issubstituted by fluoro;

M is C₁₋₆alkoxycarbonyl, carboxy, diC₁₋₆alkylamino-C₂₋₆alkoxycarbonyl,aminocarbonyl, C₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,C₁₋₆alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,hydroxy-C_(y)H_(2y)—,

R⁷ is C₁₋₆alkyl or trifluoroC₁₋₆alkyl;

y is 1-6;

or pharmaceutically acceptable salts, or tautomerism isomers thereof.

Further embodiment of present invention is (iii) a compound of formulaI, wherein

R¹ is methoxycarbonyl, ethoxycarbonyl or cyano;

R² is phenyl substituted once or twice by fluoro;

R³ is

X is oxygen or —NR⁷;

R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl; or

R⁴ and R⁵ together with the carbon atom to which they are attached formcyclopropyl; or when X is —NR⁷, one of R⁴ and R⁵ is hydrogen or methyl,and the other of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵and R⁷ are attached form:

M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl,aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl,methylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxymethyl,hydroxypropyl, —C(Me)₂OH,

R⁷ is methyl or trifluoroethyl;

or pharmaceutically acceptable salts, or tautomerism isomers thereof.

Another embodiment of present invention is (iv) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is C₁₋₂alkoxycarbonyl;

R² is phenyl which is once substituted by halogen;

R³ is 2-thiazolyl;

X is oxygen;

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl andtrifluoroC₁₋₆alkyl;

M is C₁₋₆alkoxycarbonyl or carboxy.

Further embodiment of present invention is (v) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methyoxycarbonyl;

R² is 4-fluorophenyl;

R³ is thiazol-2-yl;

X is oxygen;

R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl;

M is methoxycarbonyl or carboxy.

Another embodiment of present invention is (vi) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is C₁₋₂alkoxycarbonyl;

R² is phenyl which is once substituted by halogen;

R³ is 2-thiazolyl;

X is —N—C₁₋₆alkyl or —N-trifluoroC₁₋₆alkyl;

R⁴ is hydrogen;

R⁵ is hydrogen;

or R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3 to 7 membered cycloalkyl;

M is carboxy.

Further embodiment of present invention is (vii) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methoxycarbonyl;

R² is 4-fluorophenyl;

R³ is thiazol-2-yl;

X is —NCH₃ or —NCH₂CF₃;

R⁴ is hydrogen;

R⁵ is hydrogen;

or R⁴ and R⁵, together with the carbon atom to which they are attached,form cyclopropyl;

M is carboxy.

Another embodiment of present invention is (viii) a compound of formulaI or a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl which is once or twice substituted by halogen;

R³ is 2-thiazolyl; or 2-pyridinyl, which is once substituted by halogen;or 2-imidazolyl, which is once substituted by C₁₋₆alkyl;

X is —NR⁷;

one of R⁴ and R⁵ is hydrogen, and the other of R⁴ and R⁵ along with R⁷and the atoms to which R⁴ or R⁵ and R⁷ are attached form a morpholinyl;

M is C₁₋₆alkoxycarbonyl, carboxy or hydroxy-C_(y)H_(2y)—;

y is 1-6.

Further embodiment of present invention is (ix) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methoxycarbonyl, ethoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is thiazol-2-yl, 5-fluoro-pyridin-2-yl or 1-methyl-imidiazolid-2-yl;

one of R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷are attached form:

M is methoxycarbonyl, carboxy or hydroxymethyl-.

Another embodiment of present invention is (x) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl which is once or twice substituted by halogen;

R³ is 2-thiazolyl, which is unsubstituted or once substituted byC₁₋₆alkyl or halogen; or 2-thienyl or 2-pyridinyl, which is oncesubstituted by halogen; or 2-imidazolyl, which is once substituted byC₁₋₆alkyl; or 3-isoxazolyl, which is unsubstituted or once substitutedby C₁₋₆alkyl;

X is —NR⁷;

one of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the other of R⁴ and R⁵along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form apyrrolidinyl or piperidinyl, which is substituted by fluoro;

M is C₁₋₆alkoxycarbonyl, carboxy, diC₁₋₆alkylaminoC₂₋₆alkoxycarbonyl,aminocarbonyl, C₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,C₁₋₆alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,hydroxy-C_(y)H_(2y)—,

y is 1-6.

Further embodiment of present invention is (xi) a compound of formula Ior a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methoxycarbonyl, ethoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is

X is —NR⁷;

one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴ and R⁵ alongwith R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form

M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl,aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl,methylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxymethyl,hydroxypropyl, —C(Me)₂OH,

Another embodiment of present invention is (xii) a compound of formulaI′ or a pharmaceutically acceptable salt or tautomerism isomers thereof,

wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl, which is substituted by halogen;

R³ is 2-thiazolyl which is unsubstituted or substituted by C₁₋₆alkyl or2-pyridinyl, which is substituted by halogen;

X is oxygen or —NR⁷;

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl andtrifluoroC₁₋₆alkyl; or

R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3 to 7 membered cycloalkyl; or

when X is —NR⁷, one of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the otherof R⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ areattached form a morpholinyl; or pyrrolidinyl substituted by fluoro;

R⁶ is hydrogen or C₁₋₆alkyl;

R⁷ is C₁₋₆alkyl.

Further embodiment of present invention is (xiii) a compound of formulaI′ or a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methoxycarbonyl or cyano;

R² is phenyl substituted once or twice by fluoro;

R³ is thiazol-2-yl, 5-methyl-thiazol-2-yl or 5-fluoro-pyridin-2-yl; or;

X is oxygen or —NR⁷;

R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl; or

R⁴ and R⁵ together with the carbon atom to which they are attached formcyclopropyl; or

when X is —NR⁷, one of R⁴ and R⁵ is hydrogen or methyl and the other ofR⁴ and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ areattached form

R⁶ is hydrogen or methyl;

R⁷ is methyl.

Still further embodiment of present invention is (xiv) a compound offormula I′ or a pharmaceutically acceptable salt or tautomerism isomersthereof, wherein

R¹ is C₁₋₂alkoxycarbonyl;

R² is phenyl which is substituted by halogen;

R³ is 2-thiazolyl;

X is oxygen;

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₆alkyl andtrifluoroC₁₋₆alkyl;

R⁶ is hydrogen or C₁₋₆alkyl.

More further embodiment of present invention is (xv) a compound offormula I′ or a pharmaceutically acceptable salt or tautomerism isomersthereof, wherein

R¹ is methyoxycarbonyl;

R² is 4-fluorophenyl;

R³ is thiazolidin-2-yl;

X is oxygen;

R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl;

R⁶ is hydrogen or methyl.

Another further embodiment of present invention is (xvi) a compound offormula I′ or a pharmaceutically acceptable salt or tautomerism isomersthereof, wherein

R¹ is C₁₋₂alkoxycarbonyl;

R² is phenyl which is substituted by halogen;

R³ is 2-thiazolyl;

X is NC₁₋₆alkyl;

R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3 to 7 membered cycloalkyl;

R⁶ is hydrogen.

Further embodiment of present invention is (xvii) a compound of formulaI′ or a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methoxycarbonyl;

R² is 4-fluorophenyl;

R³ is thiazolidin-2-yl;

X is —NCH₃;

R⁴ and R⁵, together with the carbon atom to which they are attached,form cyclopropyl;

R⁶ is hydrogen.

More further embodiment of present invention is (xviii) a compound offormula I′ or a pharmaceutically acceptable salt or tautomerism isomersthereof, wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl which is substituted by halogen;

R³ is 2-thiazolyl; or 2-pyridinyl, which is substituted by halogen;

X is —NR⁷;

one of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the other of R⁴ and R⁵along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form

R⁶ is hydrogen or C₁₋₆alkyl.

Further embodiment of present invention is (xix) a compound of formulaI′ or a pharmaceutically acceptable salt or tautomerism isomers thereof,wherein

R¹ is methoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is thiazolidin-2-yl or 5-fluoro-pyridin-2-yl., one of R⁴ and R⁵ ishydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and theatoms to which R⁴ or R⁵ and R⁷ are attached form

R⁶ is hydrogen or methyl.

Still further embodiment of present invention is (xx) a compound offormula I′ or a pharmaceutically acceptable salt or tautomerism isomersthereof, wherein

R¹ is C₁₋₂alkoxycarbonyl or cyano;

R² is phenyl which is substituted by halogen;

R³ is 2-thiazolyl which is unsubstituted or substituted by C₁₋₆alkyl or2-pyridinyl, which is substituted by halogen;

X is —NR⁷;

one of R⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the other of R⁴ and R⁵along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached formpyrrolidinyl substituted by fluoro;

R⁶ is hydrogen or C₁₋₆alkyl.

Another further embodiment of present invention is (xxi) a compound offormula I′ or a pharmaceutically acceptable salt or tautomerism isomersthereof, wherein

R¹ is methoxycarbonyl or cyano;

R² is 4-fluorophenyl or 3,4-difluorophenyl;

R³ is thiazol-2-yl, 5-methyl-thiazol-2-yl or 5-fluoro-pyridin-2-yl; or;

X is —NR⁷;

one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴ and R⁵ alongwith R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form

R⁶ is hydrogen or methyl.

Particular compounds of formula I, including their activity data, NMRdata and MS data are summarized in the following Table 1 and 2.

TABLE 1 Structure, name and activity data of particular compoundsHepDe19 Example EC50 CC50 No. Structure Name (μM) (μM)  1

4-(4-Fluoro-phenyl)-6- (1-methoxycarbonyl-1- methyl-ethoxymethyl)-4-methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid methylester 26.29 >100  2

6-(1-Carboxy-2,2,2- trifluoro-ethoxymethyl)- 4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acid methylester 24.43 >100  3

6-{[(1-Carboxy- cyclopropyl)-methyl- amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl- 2-thiazol-2-yl-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 21.31 >100  4

4-[6-(4-Fluoro-phenyl)- 5-methoxycarbonyl-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3- carboxylic acid1.46 >100  5

4-[6-(4-Fluoro-phenyl)- 5-methoxycarbonyl-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine- (S)-3-carboxylic acidmethyl ester 0.7 >100  6

4-[6-(4-Fluoro-phenyl)- 5-methoxycarbonyl-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine- (S)-3-carboxylic acid1.2 >100  7

(S)-4-[6-(4-Fluoro- phenyl)-5- methoxycarbonyl-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine- (S)-3-carboxylic acid0.77 >100  8

(S)-4-[6-(4-Fluoro- phenyl)-5- methoxycarbonyl-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine- (R)-3-carboxylic acid3.01 >100  9

4-[6-(4-Fluoro-phenyl)- 2-(5-fluoro-pyridin-2-yl)- 5-methoxycarbonyl-6-methyl-3,6-dihydro- pyrimidin-4-ylmethyl]- morpholine-(R)-3- carboxylicacid 4.18 >100 10

4-[6-(4-Fluoro-phenyl)- 2-(5-fluoro-pyridin-2-yl)- 5-methoxycarbonyl-6-methyl-3,6-dihydro- pyrimidin-4-ylmethyl]- morpholine-(S)-3- carboxylicacid 7.04 >100 11

6-(2-(S)-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 0.46 95.5 12

6-(2-(R)-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 6.59 82 13

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 0.15 >100 14

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(3,4-difluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.2 >100 15

4-[(S)-6-(3,4-Difluoro- phenyl)-5- methoxycarbonyl-6-methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3-carboxylic acid methyl ester 0.56 >100 16

4-[6-(3,4-Difluoro- phenyl)-5- methoxycarbonyl-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3- carboxylic acid0.25 >100 17

6-(4,4-Difluoro-2- methoxycarbonyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5- fluoro-pyridin-2-yl)-4- methyl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.59 90 18

6-(2-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro- pyridin-2-yl)-4-methyl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.57 25 19

6-(2-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5- methyl-thiazol-2-yl)-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 16.7 >100 20

(S)-6-((S)-2-Carboxy- 4,4-difluoro-2-methyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 2.8 >100 21

(S)-1-[(S)-5-Cyano-6-(4- fluoro-phenyl)-6-methyl- 2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-4,4-difluoro- pyrrolidine-2-carboxylicacid 21 >100 22

(S)-4-[5-Cyano-6-(3,4- difluoro-phenyl)-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3- carboxylic acid20.4 >100 23

(S)-1-[(S)-5-Cyano-6- (3,4-difluoro-phenyl)-6- methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4- ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic acid 7 >100 24

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(3,4-difluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester 0.8 100 25

(S)-6-(2-Carboxy-5,5- difluoro-piperidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 1.09 100 26

(S)-6-(2-Carboxy-4,4- difluoro-piperidin-1- ylmethyl)4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 1.97 100 27

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(1- methyl-1H-imidazol-2- yl)-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 2.72 55.8 28

(R)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(3,4-difluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid ethyl ester 7.48 100 29

(S)-4-[6-(3,4-Difluoro- phenyl)-5- ethoxycarbonyl-6-methyl-2-thiazol-2-yl- 3,6-dihydro-pyrimidin-4- ylmethyl]-morpholine-3-carboxylic acid 3.98 100 30

(S)-4-[(S)-6-(4-Fluoro- phenyl)-5- methoxycarbonyl-6-methyl-2-(1-methyl-1H- imidazol-2-yl)-3,6- dihydro-pyrimidin-4-ylmethyl]-morpholine-3- carboxylic acid 6.77 100 31

(R)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4- methyl-thiazol-2-yl)-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 1.67 100 32

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4- methyl-thiazol-2-yl)-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 0.13 75 33

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-2-(5-chloro-thiazol-2-yl)-4-(4-fluoro- phenyl)-4-methyl-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 2.07 80 34

(S)-6-((2S,4R)-2- Carboxy-4-fluoro- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 2.84 100 35

6-((S)-2-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-2-isoxazol-3-yl- 4-methyl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 15 100 36

(R)-6-((S)-2-Carboxy- 4,4-difluoro-2-methyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 7.49 100 37

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5- methyl-thiazol-2-yl)-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 0.47 85 38

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro- thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 2.03 39

(S)-6-((2S,4S)-2- Carboxy-4-fluoro- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 10.5 100 40

6-((S)-2-Carboxy-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5- methyl-isoxazol-3-yl)- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 5.39 100 41

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro- thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.285 100 42

(R)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro- thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 6.81 100 43

(S)-6-((S)-2-Carboxy- 4,4-difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-2-(4-fluoro- thiophen-2-yl)-4-methyl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.131 100 44

(S)-6-{[Carboxymethyl- (2,2,2-trifluoro-ethyl)- amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl- 2-thiazol-2-yl-1,4- dihydro-pyrimidine-5-carboxylic acid methyl ester 21.5 100 45

(S)-6-((S)-4,4-Difluoro- 2-methoxycarbonyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.783 100 46

(S)-6-[(S)-2-(2- Dimethylamino- ethoxycarbonyl)-4,4-difluoro-pyrrolidin-1- ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylic acid methyl ester 2.13100 47

(S)-6-(2-Carbamoyl-4,4- difluoro-pyrrolidin-1- ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro- pyrimidine-5-carboxylicacid methyl ester 0.048 100 48

(S)-6-((S)-2-Carbamoyl- 4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.08 100 49

(S)-6-((S)-2- Dimethylcarbarnoyl-4,4- difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.29 100 50

6-((S)-4,4-Difluoro-2- methylcarbamoyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.606 100 51

(S)-6-((S)-4,4-Difluoro- 2- methanesulfonylaminocarbonyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro- phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 18.16 90 52

(S)-6-[(S)-4,4-Difluoro- 2-(thiazol-2- ylcarbamoyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 5.426 4.07 53

4-(4-Fluoro-phenyl)-6- ((R)-3-hydroxymethyl- morpholin-4-ylmethyl)-4-methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine- 5-carboxylic acidmethyl ester 1.75 100 54

(S)-6-[(S)-4,4-Difluoro- 2-(1-hydroxy-1-methyl- ethyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro- phenyl)-4-methyl-2- thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.7 50.4 55

(S)-6-((S)-4,4-Difluoro- 2-hydroxymethyl- pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.067 100 56

(S)-6-[4,4-Difluoro-2-(3- hydroxy-propyl)- pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 0.66 90 57

(S)-6-[(S)-4,4-Difluoro- 2-(5-methyl- [1,3,4]oxadiazol-2-yl)-pyrrolidin-1-ylmethyl]-4- (4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine- 5-carboxylic acid methyl ester 1.558 100 58

(S)-6-[(S)-4,4-Difluoro- 2-(1H-tetrazol-5-yl)- pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl- 1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester 1.017 100 59

(S)-6-[(S)-4,4-Difluoro- 2-(3-methyl- [1,2,4]oxadiazol-5-yl)-pyrrolidin-1-ylmethyl]-4- (4-fluoro-phenyl)-4- methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine- 5-carboxylic acid methyl ester 1.238 65.3

TABLE 2 NMR and MS data of particular compounds Example No. 1H NMR dataMW 1 1H NMR (MeOD-d₄, 400 MHz), 7.95 (d, 1H, J = 3.2 Hz), MS: calc'd 462(MH+), 7.75 (d, 1H, J = 3.2 Hz), 7.49-7.45 (m, 2H), exp 462 (MH+). 7.04(t, 2H, J = 8.8 Hz), 4.71-4.62 (m, 2H), 3.80 (s, 3H), 3.43 (s, 3H), 1.92(s, 3H), 1.57 (s, 6H). 2 1H NMR (MeOD-d₄, 400 MHz), 7.94 (d, 1H, J = 2.8Hz), MS: calc'd 488 (MH+), 7.93 (d, 1H, J = 2.8 Hz), 7.53-7.49 (m, 2H),exp 488 (MH+). 7.07-7.03 (m, 2H), 4.85-4.78 (m, 2H), 4.40-4.37 (m, 1H),3.44 (s, 3H), 1.94 (s, 3H). 3 1H NMR (MeOD-d₄, 400 MHz), 8.12 (d, 1H, J= 3.2 Hz), MS: calc'd 459 (MH+), 8.06 (d, 1H, J = 3.2 Hz), 7.63-7.60 (m,2H), exp 459 (MH+). 7.15 (t, 2H, J = 8.8 Hz), 4.30 (s, 2H), 3.51 (s,3H), 2.79 (s, 3H), 2.10 (s, 3H), 1.52-1.51 (m, 2H), 1.38-1.37 (m, 2H). 41H NMR (CD3OD, 500 MHz) δ 8.10 (d, 1H), 8.03 (d, LC-MS: calc'd 1H),7.64-7.61 (m, 2H), 7.15-7.12 (m, 2H), 475 (MH+), exp 475 (MH+).4.32-4.31 (m, 2H), 4.18-4.14 (m, 2H), 3.99-3.72 (m, 3H), 3.51-3.49 (m,4H), 3.02 (m, 1H), 2.11 (d, 3H). 5 1H NMR (MeOD-d4, 400 MHz), 7.95 (d,1H, J = 3.2 Hz), MS: calc'd (MH+) 489 7.74 (d, 1H, J = 3.2 Hz),7.48-7.45 (m, 2H), exp (MH+) 489. 7.03 (t, 2H, J = 8.8 Hz), 4.05-3.87(m, 4H), 3.78-3.71 (m, 5H), 3.49-3.45 (m, 1H), 3.42 (s, 3H), 3.14-3.07(m, 1H), 2.52-2.42 (m, 1H), 1.99 (s, 3H). 6 1H NMR (MeOD-d4, 400 MHz),7.95 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 475 7.74 (d, 1H, J = 3.2 Hz),7.48-7.45 (m, 2H), exp (MH+) 475. 7.03 (t, 2H, J = 8.8 Hz), 4.35-4.21(m, 2H), 4.17-4.05 (m, 2H), 3.96-3.84 (m, 2H), 3.75-3.70 (m, 1H),3.58-3.47 (m, 4H), 2.97-2.89 (m, 1H), 1.99 (s, 3H). 7 1H NMR (MeOD-d4,400 MHz), 8.07 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 475 7.97 (d, 1H, J= 3.2 Hz), 7.62-7.59 (m, 2H), exp (MH+) 475. 7.13 (t, 2H, J = 8.8 Hz),4.31 (s, 2H), 4.17-4.05 (m, 2H), 3.96-3.84 (m, 3H), 3.62-3.55 (m, 1H),3.51 (s, 3H), 3.03-2.99 (m, 1H), 2.09 (s, 3H). 8 1H NMR (MeOD-d4, 400MHz), 8.07 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 475 7.97 (d, 1H, J =3.2 Hz), 7.62-7.59 (m, 2H), exp (MH+) 475. 7.13 (t, 2H, J = 8.8 Hz),4.28 (dd, 2H, J1 = 33.4 Hz, J2 = 16.4 Hz), 4.17-4.05 (m, 2H), 3.96-3.84(m, 3H), 3.62-3.50 (m, 4H), 3.03-2.99 (m, 1H), 2.09 (s, 3H). 9 1H NMR(MeOD-d4, 400 MHz), 8.60 (d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 4878.53-8.50 (m, 1H), 7.80-7.78 (m, 1H), exp (MH+) 487. 7.59-7.56 (m, 2H),7.11-7.07 (m, 2H), 4.11-4.01 (m, 3H), 3.99-3.97 (m, 1H), 3.88-3.84 (m,1H), 3.82-3.80 (m, 1H), 3.59-3.56 (m, 1H), 3.49 (s, 3H), 3.44-3.38 (m,1H), 2.89-2.80 (m, 1H), 2.05 (s, 3H). 10 1H NMR (MeOD-d4, 400 MHz), 8.60(d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 487 8.55-8.53 (m, 1H), 7.83-7.79(m, 1H), exp (MH+) 487. 7.60-7.57 (m, 2H), 7.13-7.08 (m, 2H), 4.17-4.08(m, 3H), 4.01-3.97 (m, 1H), 3.91-3.84 (m, 1H), 3.82-3.80 (m, 1H),3.60-3.58 (m, 1H), 3.50 (s, 3H), 3.44-3.38 (m, 1H), 2.89-2.80 (m, 1H),2.06 (s, 3H). 11 1H NMR (CD3OD, 500 MHz) δ 8.15-8.15 (m, 2H), LC-MS:calc'd 7.67-7.62 (m, 2H), 7.19-7.14 (m, 2H), 4.16-3.90 (m, 495 (MH+),exp 495 (MH+). 3H), 3.65-3.61 (m, 1H), 3.51 (d, 3H), 3.25-3.20 (m, 1H),2.86-2.82 (m, 1H), 2.63-2.61 (m, 1H), 2.15 (d, 3H). 12 1H NMR (CD3OD,500 MHz) δ 7.96 (s, 1H), 7.77 (s, LC-MS: calc'd 1H), 7.52 (d, 2H), 7.06(d, 2H), 4.00-3.95 (m, 3H), 495 (MH+), exp 495 (MH+). 3.63-3.61 (m, 1H),3.46 (s, 3H), 3.20-3.18 (m, 1H), 2.79 (m, 1H), 2.67 (m, 1H), 1.95 (s,3H). 13 1H NMR (MeOD-d4, 400 MHz), 8.21 (s, 2H), MS: calc'd (MH+) 4957.67-7.65 (m, 2H), 7.21-7.17 (m, 2H,), 4.16 (d, 1H, J = 15.6 Hz), exp(MH+) 495. 4.02 (t, 1H, J = 8.0 Hz), 3.93 (d, 1H, J = 15.6 Hz),3.72-3.61 (m, 1H), 3.53 (s, 3H), 3.29-3.19 (m, 1H), 2.91-2.78 (m, 1H),2.59-2.55 (m, 1H), 2.17 (s, 3H). 14 1H NMR (MeOD-d4, 400 MHz), 8.11 (d,1H, J = 3.2 Hz), MS: calc'd (MH+) 513.1, 8.04 (d, 1H, J = 3.2 Hz),7.55-7.49 (m, 1H), exp (MH+) 513.1 7.40-7.38 (m, 1H), 7.34-7.29 (m,1H,), 4.15 (d, 1H, J = 15.6 Hz), 4.02-3.98 (m, 2H), 3.74-3.61 (m, 1H),3.53 (s, 3H), 3.30-3.23 (m, 1H), 2.91-2.78 (m, 1H), 2.65-2.49 (m, 1H),2.08 (s, 3H). 15 1H NMR (MeOD-d4, 400 MHz), 8.17 (d, 1H, J = 3.2 Hz),MS: calc'd (MH+) 507, 8.10 (d, 1H, J = 3.2 Hz), 7.62-7.53 (m, 1H), exp(MH+) 507. 7.45-7.39 (m, 1H), 7.37-7.25 (m, 1H,), 4.25-4.18 (m, 2H),4.10-4.06 (m, 2H), 3.96-3.94 (m, 1H), 3.89-3.86 (m, 2H), 3.84 (s, 3H),3.55 (s, 3H), 3.50-3.40 (m, 1H), 2.90-2.87 (m, 1H), 2.08 (s, 3H). 16 1HNMR (MeOD-d4, 400 MHz), 8.06 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 4937.95 (d, 1H, J = 3.2 Hz), 7.53-7.51 (m, 1H), exp (MH+) 493. 7.40-7.37(m, 1H), 7.31-7.25 (m, 1H,), 4.39-4.28 (m, 2H), 4.15-4.12 (m, 2H),3.58-3.50 (m, 4H), 3.05-3.01 (m, 1H), 2.05 (s, 3H). 17 1H NMR (MeOD-d4,400 MHz), 8.80 (d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 521 8.43-8.40 (m,1H), 8.01-7.98 (m, 1H), exp (MH+) 521 7.70-7.66 (m, 2H), 7.24-7.18 (m,2H), 4.16-3.94 (m, 3H), 3.84-3.83 (m, 3H), 3.61-3.55 (m, 4H), 3.22-3.18(m, 1H), 2.91-2.78 (m, 1H), 3.61-3.48 (m, 1H), 2.24-2.21 (m, 3H). 18 1HNMR (MeOD-d4, 400 MHz), 8.77 (d, 1H, J = 2.8 Hz), MS: calc'd (MH+) 5078.46-8.42 (m, 1H), 8.00-7.95 (m, 1H), exp (MH+) 507. 7.70-7.66 (m, 2H),7.23-7.19 (m, 2H), 4.16 (d, 1H, J = 16 Hz), 3.98 (t, 1H, J = 8.8 Hz),3.88 (d, 1H, J = 16 Hz), 3.60-3.56 (m, 4H), 3.28-3.15 (m, 1H), 2.93-1.79(m, 1H), 2.58-44 (m, 1H), 2.21 (s, 3H). 19 ¹H NMR (400 MHz, MeOH-d4)7.87 (s, 1 H), MS: calc'd (MH+) 509 7.47-7.51 (m, 2 H), 7.01-7.06 (m, 2H), 3.92-4.30 (m, 2 exp (MH+) 509. H), 3.49 (s, 3 H), 3.40 (m, 2H),2.35-2.90 (m, 3 H), 2.36 (s, 3 H), 1.85 (s, 3 H). 20 ¹H NMR (400 MHz,MeOH-d4) 8.02-8.18 (m, 2 H), MS: calc'd (MH+) 509 7.54-7.65 (m, 2 H),7.08-7.20 (m, 2 H), exp (MH+) 509. 3.88-4.14 (m, 2 H), 3.49 (s, 3 H),2.75-2.90 (m, 2 H), 2.41-2.57 (m, 2 H), 2.09 (s, 3 H), 1.56 (s, 3 H). 211H NMR (MeOD-d4, 400 MHz), 7.98 (d, 1H, J = 3.2 Hz), MS: calc'd (M+ + H)462, 7.81 (d, 1H, J = 3.2 Hz), 7.57-7.53 (m, 2H), exp (M+ + H) 462. 7.14(t, 2H, J = 8.8 Hz), 3.92-3.74 (m, 3H), 3.49-3.41 (m, 1H), 3.18-3.08 (m,1H), 2.81-2.69 (m, 1H), 2.55-2.49 (m, 1H), 1.89 (s, 3H). 22 1H NMR(MeOD-d4, 400 MHz), 8.03 (d, 1H, J = 3.2 Hz), MS: calc'd (MH+) 460 7.88(d, 1H, J = 3.2 Hz), 7.45-7.42 (m, 1H), exp (MH+) 460. 7.36-7.30 (m,2H), 4.16-4.01 (m, 4H), 3.96-3.82 (m, 3H), 3.43-3.37 (m, 1H), 2.93-2.86(m, 1H), 1.92 (s, 3H). 23 1H NMR (MeOD-d4, 400 MHz), 7.98 (d, 1H, J =3.2 Hz), MS: calc'd (MH+) 480 7.81 (d, 1H, J = 3.2 Hz), 7.44-7.39 (m,1H), exp (MH+) 480. 7.35-7.27 (m, 2H), 3.92-3.74 (m, 3H), 3.49-3.41 (m,1H), 3.18-3.08 (m, 1H), 2.81-2.69 (m, 1H), 2.52-2.46 (m, 1H), 1.86 (s,3H). 24 ¹H NMR (MeOD-d₄, 400 MHz), 7.95 (d, J = 3.01 Hz, MS: calc'd(MH+) 527 1 H), 7.73 (d, J = 3.26 Hz, 1 H), 7.37 (ddd, J = 12.17, exp(MH+) 527. 7.78, 1.88 Hz, 1 H), 7.28 (br. s., 1 H), 7.17-7.26 (m, 1 H),3.85-4.06 (m, 4 H) 3.69 (t, J = 8.16 Hz, 1 H) 3.48-3.61 (m, 1 H)2.99-3.18 (m, 1 H) 2.61-2.78 (m, 1 H) 2.39-2.58 (m, 1 H) 1.89 (s, 3H)1.04 (t, J = 7.03 Hz, 3 H). 25 ¹H NMR (MeOD-d₄, 400 MHz), 8.25 (s, 2H), MS: calc'd (MH+) 509 7.58-7.75 (m, 2 H), 7.19 (t, J = 8.66 Hz, 2 H),exp (MH+) 509. 3.93-4.19 (m, 2 H), 3.75 (d, J = 1.25 Hz, 1 H), 3.53 (s,3 H), 3.35-3.46 (m, 1 H), 2.88-3.10 (m, 1 H), 1.85-2.41 (m, 7 H). 26 ¹HNMR (MeOD-d₄, 400 MHz), 7.97 (d, J = 3.01 Hz, MS: calc'd (MH+) 509 1 H),7.72 (d, J = 3.01 Hz, 1 H), 7.49 (dd, J = 8.66, exp (MH+) 509. 5.40 Hz,2 H), 7.04 (t, J = 8.78 Hz, 2 H), 3.72-3.87 (m, 2 H), 3.44 (s, 3 H),3.25-3.31 (m, 1 H), 3.14 (d, J = 12.05 Hz, 1 H), 2.47-2.60 (m, 1 H),1.97-2.41 (m, 4 H), 1.89 (s, 3 H). 27 ¹H NMR (MeOD-d₄, 400 MHz), 7.53(dd, J = 8.66, MS: calc'd (MH+) 492 5.40 Hz, 2 H), 7.19 (s, 1 H),6.98-7.11 (m, 3 H), exp (MH+) 492. 3.77-3.96 (m, 5 H), 3.51-3.65 (m, 2H), 3.46 (s, 3 H), 3.01 (td, J = 15.12, 11.42 Hz, 1 H), 2.64 (qd, J =12.84, 8.16 Hz, 1 H), 2.32-2.50 (m, 1 H), 1.84-2.00 (m, 3 H). 28 ¹H NMR(MeOD-d₄, 400 MHz), 7.95 (d, J = 3.01 Hz, MS: calc'd (MH+) 527 1 H),7.72 (d, J = 3.26 Hz, 1 H), 7.36 (ddd, J = 12.30, exp (MH+) 527. 7.78,2.26 Hz, 1 H), 7.27 (br. s., 1 H), 7.21 (dd, J = 10.29, 8.28 Hz, 1 H),3.80-4.02 (m, 4 H), 3.44-3.58 (m, 2 H), 2.87 (td, J = 15.56, 11.04 Hz, 1H), 2.54-2.73 (m, 1 H), 2.35-2.52 (m, 1 H), 1.89 (s, 3 H), 1.03 (t, J =7.03 Hz, 3 H). 29 ¹H NMR (MeOD-d₄, 400 MHz), 8.10 (d, J = 2.76 Hz, MS:calc'd (MH+) 507 1 H), 7.99-8.06 (m, 1 H), 7.52-7.63 (m, 1 H), exp (MH+)507. 7.44 (d, J = 7.03 Hz, 1 H), 7.22-7.38 (m, 1 H), 5.36 (t, J = 4.64Hz, 1 H), 4.30-4.54 (m, 2 H), 4.09-4.22 (m, 3 H), 3.86-4.06 (m, 4 H),3.55-3.73 (m, 1 H), 1.98-2.15 (m, 3 H), 0.92 (t, J = 6.78 Hz, 3 H). 30¹H NMR (MeOD-d₄, 400 MHz), 7.52 (dd, J = 8.66, MS: calc'd (MH+) 472 5.40Hz, 2 H), 7.21 (s, 1 H), 6.98-7.11 (m, 3 H), exp (MH+) 472. 3.72-4.06(m, 10 H) 3.48 (s, 3 H), 3.12-3.23 (m, 1 H), 2.61 (ddd, J = 11.54, 8.16,3.14 Hz, 1 H), 1.93 (s, 3 H). 31 ¹H NMR (CDCl₃, 400 MHz), 7.47-7.59 (m,2 H), MS: calc'd (MH+) 509 7.18 (s, 1 H), 7.01-7.12 (m, 2 H), 4.12 (d, J= 14.56 Hz, exp (MH+) 509. 1 H), 3.98 (dd, J = 9.79, 6.02 Hz, 1 H), 3.61(d, J = 14.31 Hz, 1 H), 3.53 (d, J = 10.54 Hz, 1 H), 3.47 (s, 3 H), 3.12(br. s., 1 H), 2.71-2.90 (m, 1 H), 2.50-2.67 (m, 1 H), 2.46 (s, 3 H),1.98-2.07 (m, 3 H). 32 ¹H NMR (CDCl₃, 400 MHz), 7.49-7.61 (m, 2 H), MS:calc'd (MH+) 509 7.17 (s, 1 H), 7.05-7.13 (m, 2 H), 4.14 (d, J = 14.31Hz, exp (MH+) 509. 1 H), 3.92 (dd, J = 9.66, 6.15 Hz, 1 H), 3.49-3.58(m, 2 H), 3.47 (s, 3 H), 3.18-3.33 (m, 1 H), 2.81 (dd, J = 14.68, 9.66Hz, 1 H), 2.57 (dd, J = 12.30, 6.02 Hz, 1 H), 2.46 (s, 3 H), 2.01 (s, 3H). 33 ¹H NMR (CDCl₃, 400 MHz), 7.71 (s, 1 H), MS: calc'd (MH+) 5297.41-7.58 (m, 2 H), 7.00-7.17 (m, 2 H), 4.12-4.21 (m, 1 H), exp (MH+)529. 3.93-4.03 (m, 1 H), 3.70-3.78 (m, 1 H), 3.54 (s, 4 H), 3.15-3.30(m, 1 H), 2.75-2.90 (m, 1 H), 2.52-2.69 (m, 1 H), 2.15 (s, 3 H). 34 ¹HNMR (MeOD-d₄, 400 MHz), 7.93-8.01 (m, 1 H), MS: calc'd (MH+) 4777.79-7.89 (m, 1 H), 7.55-7.67 (m, 2 H), exp (MH+) 477. 7.06-7.17 (m, 2H), 5.45-5.58 (m, 1 H), 5.31-5.45 (m, 1 H), 3.81-4.12 (m, 2 H), 3.48 (s,3 H), 2.70-2.94 (m, 2 H), 2.31-2.55 (m, 2 H), 1.96-2.10 (m, 3 H). 35 ¹HNMR (MeOD-d₄, 400 MHz), 8.80-8.87 (m, 1 H), MS: calc'd (MH+) 4797.48-7.59 (m, 2 H), 7.10 (s, 3 H), 3.77-4.10 (m, 3 exp (MH+) 479. H),3.48-3.62 (m, 1 H), 3.46 (d, J = 4.27 Hz, 3 H), 3.00-3.23 (m, 1 H),2.70-2.87 (m, 1 H), 2.42-2.64 (m, 1 H), 1.98 (d, J = 3.51 Hz, 3 H). 36¹H NMR (MeOD-d₄, 400 MHz), 8.14-8.17 (m, 1 H), MS: calc'd (MH+) 5098.10-8.13 (m, 1 H), 7.58-7.65 (m, 2 H), exp (MH+) 509. 7.11-7.19 (m, 2H), 3.99-4.06 (m, 2 H), 3.52 (s, 4 H), 3.35-3.38 (m, 1 H), 2.75-2.89 (m,1 H), 2.41-2.56 (m, 1 H), 2.12 (s, 3 H), 1.56 (s, 3 H). 37 ¹H NMR(MeOD-d₄, 400 MHz), 7.62 (s, 1H), 7.50 (dd, MS: calc'd (MH+) 509 J =5.40, 8.66 Hz, 2H), 7.05 (t, J = 8.78 Hz, 2H), exp (MH+) 509. 3.90 (d, J= 5.77 Hz, 2H), 3.65 (t, J = 8.28 Hz, 1H), 3.39-3.58 (m, 7H), 3.05 (d, J= 11.54 Hz, 1H), 2.68 (dd, J = 7.91, 13.18 Hz, 1H), 2.48-2.58 (m, 4H).38 ¹H NMR (MeOD-d₄, 400 MHz), 7.62 (t, J = 3.9 Hz, 1 MS: calc'd (MH+)512 H), 7.46 (dd, J = 8.7, 5.4 Hz, 2 H), 7.02 (t, J = 8.8 Hz, exp(MH+)512. 2 H), 6.59 (dd, J = 4.3, 1.8 Hz, 1 H), 3.86 (d, J = 14.3 Hz, 2H), 3.75 (t, J = 6.5 Hz, 1 H), 3.41-3.62 (m, 6 H), 3.06 (q, J = 7.3 Hz,2 H), 2.61 (dd, J = 16.1, 7.5 Hz, 1 H), 2.26-2.45 (m, 1 H). 39 ¹H NMR(MeOD-d₄, 400 MHz), 7.96 (d, J = 3.0 Hz, 1 MS: calc'd (MH+) 477 H), 7.85(d, J = 3.3 Hz, 1 H), 7.65 (dd, J = 8.8, 5.3 Hz, exp (MH+)477. 2 H),7.13 (t, J = 8.8 Hz, 2 H), 5.29-5.52 (m, 1 H), 4.62 (d, J = 14.1 Hz, 1H), 4.39 (d, J = 9.5 Hz, 1 H), 4.08-4.27 (m, 2 H), 3.44-3.69 (m, 5 H),2.54-2.97 (m, 3 H). 40 ¹H NMR (MeOD-d₄, 400 MHz), 7.51 (dd, J = 8.2, 5.4Hz, MS: calc'd (MH+) 493 2 H), 7.06 (q, J = 8.8 Hz, 2 H), 6.61 (d, J =4.0 Hz, exp (MH+)493. 1 H), 3.72-3.96 (m, 2 H), 3.40-3.63 (m, 6 H),2.82-3.12 (m, 2 H), 2.57-2.76 (m, 1 H), 2.35-2.52 ppm (m, 5 H). 41 ¹HNMR (CDCl₃, 400 MHz), 7.53 (m, 2H), 7.43 (m, MS: calc'd (MH+) 512 1H),7.08 (m, 2H), 6.85 (d, 1H, J = 5.6 Hz), 4.08 (d, exp (MH+) 512. 1H, J =14.2 Hz), 3.86 (1H, m), 3.57 (d, 1H, J = 14.2 Hz), 3.50 (1H, m), 3.45(3H, s), 3.20 (1H, m), 2.77 (1H, m), 2.54 (1H, m), 1.97 (3H, s). 42 ¹HNMR (CDCl₃, 400 MHz), 7.52 (m, 2H), MS: calc'd (MH+) 512 7.42 (m, 1H),7.06 (m, 2H), 6.84 (d, 1H, J = 5.6 Hz), exp (MH+) 512. 4.05 (d, 1H, J =14.2 Hz), 3.91 (m, 1H), 3.64 (d, 1H, J = 14.2 Hz), 3.47 (m, 1H), 3.45(3H, s), 3.10 (m, 1H), 2.78 (m, 1H), 2.55 (m, 1H), 1.98 (s, 3H). 43 ¹HNMR (CDCl₃, 400 MHz), 7.70 (s, 1H), 7.45 (m, MS: calc'd (MH+) 512 2H),7.00 (m, 3H), 4.07 (d, 1H, J = 15.0 Hz), 3.72 (m, exp (MH+) 512. 1H),3.55 (s, 3H), 3.54-3.34 (m, 2H), 3.07 (m, 1H), 2.68 (m, 1H), 2.32 (m,1H), 2.01 (s, 3H). 44 ¹H NMR (MeOD-d₄, 400 MHz), □7.95 (d, J = 3.26 Hz,MS: calc'd (MH+) 501 1 H), 7.75 (d, J = 3.26 Hz, 1 H), 7.44-7.54 (m, 2H), exp (MH+) 501. 7.05 (t, J = 8.78 Hz, 2 H), 3.90-4.09 (m, 2H), 3.63(s, 2 H), 3.45 (s, 3 H), 1.91 (s, 3 H). 45 ¹H NMR (MeOD-d₄, 400 MHz),8.23 (d, J = 0.75 Hz, MS: calc'd (MH+) 509 2 H), 7.61-7.70 (m, 2 H),7.19 (t, J = 8.66 Hz, 2 H), exp (MH+) 509. 4.06-4.16 (m, 1 H), 4.02 (t,J = 8.03 Hz, 1H), 3.92 (d, J = 15.81 Hz, 1 H), 3.82 (s, 3 H), 3.59 (d, J= 10.79 Hz, 1 H), 3.53 (s, 3 H), 3.12-3.28 (m, 1 H), 2.72-2.89 (m, 1 H),2.43-2.61 (m, 1 H), 2.16 (s, 3 H). 46 ¹H NMR (MeOD-d₄, 400 MHz), 7.94(d, J = 3.01 Hz, MS: calc'd (MH+) 566 1 H), 7.74 (d, J = 3.01 Hz, 1 H),7.49 (br. s., 2 H), exp (MH+) 566. 7.05 (t, J = 8.78 Hz, 2 H), 4.33 (t,J = 5.65 Hz, 2 H), 3.94 (s, 3 H), 3.42-3.56 (m, 5 H), 2.66-2.82 (m, 4H), 2.33 (s, 6 H), 1.90 (s, 3 H). 47 ¹H NMR (MeOD-d₄, 400 MHz), 7.95(br. s., 1 H) MS: calc'd (MH+) 494 7.69-7.84 (m, 1 H) 7.61 (dd, J =8.28, 5.52 Hz, 1 H) exp (MH+) 494. 7.48 (dd, J = 8.03, 5.52 Hz, 1 H)6.99-7.17 (m, 2 H) 3.39-3.88 (m, 6 H) 2.91-3.30 (m, 2 H) 2.62-2.86 (m, 1H) 2.22-2.53 (m, 1 H) 1.81-2.02 (m, 3 H). 48 ¹H NMR (MeOD-d₄, 400 MHz),8.13-8.00 (m, 1 H) MS: calc'd (MH+) 494 7.98-7.82 (m, 1 H) 7.59 (br. s.,2 H) 7.13 (s, 2 H) exp (MH+) 494.1. 3.96-3.82 (m, 1 H) 3.80-3.64 (m, 2H) 3.62-3.44 (m, 4 H) 3.24-3.07 (m, 1 H) 2.84-2.66 (m, 1 H) 2.49-2.26(m, 1 H) 2.02 (s, 3 H). 49 ¹H NMR (MeOD-d₄, 400 MHz), 8.10-7.98 (m, 1 H)MS: calc'd (MH+) 522 7.94-7.76 (m, 1 H) 7.62-7.43 (m, 2 H) 7.10 (s, 2 H)exp (MH+) 522.0. 4.27 (s, 1 H) 3.95 (s, 1 H) 3.76-3.53 (m, 2 H) 3.47 (s,3 H) 3.09 (s, 4 H) 3.00 (s, 3 H) 2.91-2.75 (m, 1 H) 2.43-2.21 (m, 1 H)1.97 (s, 3 H). 50 ¹H NMR (MeOD-d₄, 400 MHz), 8.05-7.89 (m, 1 H) MS:calc'd (MH+) 508 7.87-7.69 (m, 1 H) 7.66-7.33 (m, 2 H) 7.07 (br. s., 2exp (MH+) 508.2. H) 3.92-3.59 (m, 3 H) 3.57-3.39 (m, 4 H) 3.27-2.95 (m,1 H) 2.90-2.58 (m, 4 H) 2.39-2.23 (m, 1 H) 2.02-1.77 (m, 3 H). 51 ¹H NMR(MeOD-d₄, 400 MHz), 8.14-8.03 (m, 1 H) MS: calc'd (MH+) 572 8.00-7.91(m, 1 H) 7.65-7.51 (m, 2 H) 7.11 (s, 2 H) exp (MH+) 572.2. 4.03-3.81 (m,3 H) 3.63 (d, J = 11.04 Hz, 1 H) 3.50 (s, 3 H) 3.28-3.10 (m, 1 H)291-2.73 (m, 1 H) 2.68 (s, 3 H) 2.49 (qd, J = 14.01, 7.15 Hz, 1 H) 2.06(s, 3 H). 52 ¹H NMR (MeOD-d₄, 400 MHz), 8.00-7.84 (m, 1 H) MS: calc'd(MH+) 577 7.82-7.62 (m, 1 H) 7.60-7.29 (m, 3 H) 7.13 (br. s., 1 exp(MH+) 577.3. H) 7.03 (br. s., 2 H) 4.10-3.76 (m, 3 H) 3.72-3.55 (m, 1 H)3.45 (s, 3 H) 3.25-3.08 (m, 1 H) 2.95-2.73 (m, 1 H) 2.63-2.35 (m, 1 H)1.97-1.64 (m, 3 H). 53 ¹H NMR (MeOD-d₄, 400 MHz), 7.86-8.06 (m, 2 H) MS:calc'd (MH+) 461 7.63 (dd, J = 8.53, 5.27 Hz, 2 H) 7.13 (t, J = 8.16 Hz,2 exp (MH+) 461. H) 4.41-4.73 (m, 2 H) 4.02-4.24 (m, 2 H) 3.87-3.98 (m,3 H) 3.72-3.65 (m, 2 H) 3.35-3.55 (m, 5 H) 2.09 (d, J = 4.52 Hz, 3 H).54 ¹H NMR (CDCl₃, 400 MHz), 7.81-7.91 (m, 1 H), MS: calc'd (MH+) 5097.38-7.66 (m, 3 H), 7.03 (br. s., 2 H), 4.10-4.28 (m, exp (MH+) 509. 1H), 3.88-4.09 (m, 1 H), 3.45-3.59 (m, 3 H), 3.29-3.45 (m, 1 H), 3.23 (t,J = 8.41 Hz, 1 H), 2.87-3.09 (m, 1 H), 2.41 (dd, J = 14.31, 7.28 Hz, 1H), 2.19 (s, 1 H), 1.86-2.00 (m, 3 H), 1.18-1.33 (m, 6 H). 55 ¹H NMR(CDCl₃, 400 MHz), 7.86 (d, 1H, J = 3.1 Hz), MS: calc'd (MH+) 481 7.52(m, 3H), 7.02 (m, 2H), 4.04 (m, 1H), 3.79 (m, exp (MH+) 481. 2H), 3.52(s, 3H), 3.52 (m, 2H), 3.16 (m, 1H), 3.00 (m, 1H), 2.40 (m, 2H), 1.98(s, 3H). 56 ¹H NMR (MeOD-d₄, 400 MHz), 7.95 (d, J = 4.0 Hz, MS: calc'd(MH+) 509 1H), 7.75 (d, J = 4.0 Hz, 1H), 7.51-7.47 (m, 2H), exp (MH+)509. 7.05 (t, J = 8.0 Hz, 2H), 3.96 (d, J = 16 Hz, 1H), 3.74 (d, J = 16Hz, 1H), 3.58 (t, J = 6.0 Hz, 2H), 3.50-3.40 (m, 1H), 3.48 (s, 3H),2.98-2.85 (m, 2H), 2.57-2.45 (m, 1H), 2.13-2.05 (m, 1H), 1.92-1.85 (m,1H), 1.90 (s, 3H), 1.63-1.49 (m, 3H). 57 ¹H NMR (MeOD-d₄, 400 MHz), 7.97(br. s., 1 H) MS: calc'd (MH+) 533 7.83-7.68 (m, 1 H) 7.44 (br. s., 2 H)7.03 (br. s., 2 H) exp (MH+) 533.2. 4.55-4.37 (m, 1 H) 3.97 (d, J = 3.26Hz, 2 H) 3.67-3.53 (m, 1 H) 3.45 (s, 3 H) 3.27-3.13 (m, 1 H) 2.96-2.66(m, 2 H) 2.36 (s, 3 H) 1.84 (s, 3 H). 58 ¹H NMR (MeOD-d₄, 400 MHz),8.02-7.92 (m, 1 H) MS: calc'd (MH+) 519 7.77 (d, J = 3.01 Hz, 1 H) 7.48(dd, J = 8.53, 5.27 Hz, exp (MH+) 519.1. 2 H) 7.05 (t, J = 8.66 Hz, 2 H)4.50 (t, J = 8.28 Hz, 1 H) 3.72-3.57 (m, 2 H) 3.41 (s, 3 H) 3.24-3.08(m, 2 H) 2.80 (td, J = 15.75, 7.15 Hz, 2 H) 1.85 (s, 3 H). 59 ¹H NMR(MeOD-d₄, 400 MHz), 7.95 (d, J = 3.01 Hz, 1 MS: calc'd (MH+) 533 H) 7.74(d, J = 3.26 Hz, 1 H) 7.47 (dd, J = 8.66, 5.40 Hz, exp (MH+) 533.2. 2 H)7.04 (t, J = 8.78 Hz, 2 H) 4.53 (t, J = 7.91 Hz, 1 H) 3.95 (d, J = 8.53Hz, 2 H) 3.60 (d, J = 10.79 Hz, 1 H) 3.50-3.39 (m, 3 H) 3.26 (br. s., 1H) 2.99-2.85 (m, 1 H) 2.78-2.64 (m, 1 H) 2.35 (s, 3 H) 1.90-1.81 (m, 3H).

More particular compounds of formula I include the following:

-   4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic    acid;-   4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic    acid;-   (S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic    acid;-   (S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic    acid;-   4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylic    acid;-   4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylic    acid;-   6-(2-(S)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-(2-(R)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   4-[6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylic    acid;-   6-(4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-(2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-(2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-1-[(S)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylic    acid;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (S)-6-(2-Carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-(2-Carboxy-4,4-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-(5-chloro-thiazol-2-yl)-4-(4-fluoro-phenyl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(4-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-(2-Carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-2-Dimethylcarbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-[(S)-4,4-Difluoro-2-(thiazol-2-ylcarbamoyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-[(S)-4,4-Difluoro-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-((S)-4,4-Difluoro-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-[(S)-4,4-Difluoro-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (S)-6-[(S)-4,4-Difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester; and-   (S)-6-[(S)-4,4-Difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester.

It is very important for a drug to have a moderate or low clearance, asthis often lead to a good oral bioavailability and high exposure intarget organ. Reducing the clearance of a compound or drug could thenpotentially reduce drastically the daily dose required for efficacy andtherefore give a much better safety profile as well. From the examplesbelow, it has been found a marked increase of metabolic stability andliver exposure of 4-methyldihydropyrimidines of current invention.

4-Hydrogen-dihydropyrimidines such as Bay 41-4109 can be oxidized topyrimidine product XLVI when treated with human, rat or mouse livermicrosomes. In this experiment, pooled liver microsomes (20 mg/ml) fromhuman, male Wister rat and male CD-1 mouse were obtained from BDBioscience (Franklin Lakes, N.J. USA). Incubation reaction mixturescontained a final concentration of 0.1M sodium phosphate buffer (pH7.4), 0.5 mg/ml microsomal protein, 5 μM of the tested compounds and 1mM NADPH in a total volume of 400 μl. The incubations were done for 60minutes and 300 μl of the mixtures was transferred to 150 μl of ice coldmethanol to terminate reactions. After vortexes for 3 minutes andcentrifuged at 4000 rpm at 4° C. for 10 minutes, the clear supernatantwas used directly for analysis. The samples were analyzed by AppliedBiosystems API 3200 Q TRAP LC/MS/MS system using electrospray ionizationmode.

Pyrimidine product XLVI was the major metabolite in the in vitroclearance tests (FIG. 1), and it was inactive to HBV DNA reduction inHepDE19 cell based assays with EC₅₀ value above 100 μM. On the otherhand, the 4-methyl-dihydropyrimidines series in this invention do nothave the aromatization issues of the core structure.

HBV viruses infect hepatocyte cells and replicate in the liver. To haveeffective viral suppression, it is important for an anti-HBV drug tohave sufficient exposure in the target organ. The following findingshighlight increased metabolic stability and high liver exposure of4-methyldihydropyrimidine analogs in this invention.

In this experiment, fresh mouse liver sample was homogenized by addingsaline (1 g liver tissue: 5 mL saline) immediately after collection.After centrifuging for 10 minutes at 14000 rpm, the pooled supernatantwas used to prepare liver homogenate solutions. The effective compoundsconcentrations in liver homogenate were 100, 300, and 1000 ng/mL. Then,they were incubated at rt. After incubation time of 0, 15 and 30minutes, 180 μl aliquots of MeOH was added into 20 μl of homogenate,respectively. All these samples were vortex mixed for 5 minutes at 1500rpm and centrifuged for 10 minutes at 14000 rpm. The supernatants weretransferred into a 96-well plate for LC-MS/MS analysis. The results weresummarized and showed in Table 3.

TABLE 3 The percentage of Bay 41-4109 and Example 13 remaining in mouseliver homogenate. Concentration Peak Incubation Time Percentage Compound(ng/mL) Area* (mm) to 0 min Bay41-4109 100 9263 15 1.84%  504715 0 100%300 N.D. 30  0% 1363649 0 100% 1000 7868 30 0.16%  93431 15 1.90% 4930207 0 100% Example 100 58644 15 119% 13 49480 0 100% 300 120162 30108% 111014 0 100% 1000 368388 30 86.0%  375366 15 87.6%  428458 0 100%*the data directly calculated by LC/MS/MS, the relative standardvariation is at 20%. **: not detected

By comparing the peak area of individual samples at 15 and 30 min to theone at 0 min from same concentration level, the stability of Bay41-4109and Example 13 in CD-1 mouse liver homogenate was evaluated.

It can be obviously concluded that Bay41-4109 is not stable in liverhomogenate treated with saline. About 2% of compound was detected after15 minutes room temperature incubation, at three different concentrationlevels. In samples incubated for 30 minutes, only 0.16% can be found (at1000 ng/mL. Not detected in 100 ng/mL and 300 ng/mL samples due toinstrument sensitivity).

It can be concluded that Example 13 is stable in in liver homogenatetreated with saline.

The in vivo DMPK of selected compounds were evaluated in male ICR micefollowing intravenous (or i.v.) or oral (or p.o.) administration. Insingle dose pharmacokinetics (SDPK) studies, compounds were dissolved in6% Solutol solution (Solutol:Ethanol, 1:1, v/v), and 94% 0.9% saline fori.v. dose. For p.o. administration, compounds were mixed with 0.89%microcrystalline cellulose and 0.11% carboxymethyl cellulose sodiumwater solution, or 1% RC591 as suspensions. The single dose exposurelevels of Bay 41-4109, Example 6, Example 11, Example 13 and Example 19in mouse plasma and/or liver are shown as FIG. 2-6.

Synthesis

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsas well as their starting materials are provided in the schemes belowand in the examples. All substituents, in particular, R¹ to R⁵, M and Xare as defined above unless otherwise indicated. Furthermore, and unlessexplicitly otherwise stated, all reactions, reaction conditions,abbreviations and symbols have the meanings well known to a person ofordinary skill in organic chemistry.

General synthetic scheme for 4-methyl-5-ester-6-methyl-dihydropyrimidinebased analogues Intermediate-1 (Scheme 1)

One category of the compounds described herein relates to4-methyl-5-ester-6-methyl-dihydropyrimidine based analogues with theformula Intermediate-1 wherein R⁸ is C₁₋₆alkyl.

Compound of interest Intermediate-1 can be prepared according to thegeneral synthesis method shown in Scheme 1.

Amidine III can be prepared from commercial available nitrile II,ammonium chloride and trimethyl aluminum. The reaction is typicallyperformed by adding trimethyl aluminum to the mixture of ammoniumchloride in toluene at 0° C. After 30 minutes, nitrile II is added intothe flask and the reaction mixture is stirred at 80° C. overnight.

The indium triflate catalyzed condensation reaction of commercialavailable ester IV and ethynyl-benzene V gives α,β-unsaturated ketoneVI. The reaction is typically performed in o-xylene at 120° C. for 2 h.

As an alternative method to synthesize tetra-substituted α,β-unsaturatedketone VI, especially when R⁸ is tert-butyl group. Ketone VIII can beprepared by condensation of ester IV with substituted benzaldehyde VII.The reaction is typically performed in ethanol with catalytic quantityof piperidine and acetic acid at rt overnight.

Ketone IX can be prepared by 1,4-Michael addition of methyl group to theα,β-unsaturated ketone VIII. The reaction is typically performed byadding methyl lithium solution to cuprous iodide in THF solution at 0°C. and stirred for 1 hour at 0° C., then the solution of VIII in THF isadded into the mixture at −78° C. and stirred for 1 hour at −78° C.

α,βUnsaturated ketone VI can be prepared by oxidative elimination ofketone IX. The reaction is typically performed by adding sodium hydrideinto the solution of ketone IX in THF, then phenylselenyl chloride isadded and stirred at rt for 1 hour. After the mixture is treated withpentene, ether and saturated sodium bicarbonate, the organic layer istreated with H₂O₂ solution (30%) and stirred at rt for 1 hour.

Analogs with general structure Intermediate-1 can be prepared by thecondensation reaction of α,βunsaturated ketone VI with amidine III. Thereaction is typically carried out by adding a solution of VI in NMPdropwisely into a mixture of amidine III and NaHCO₃ in NMP at 120° C.,after addition the mixture is stirred at 120° C. for half an hour beforeworkup.

General synthetic scheme for4-methyl-5-cyano-6-nitrogen-substituted-2,4-dihydro-pyrimidine basedanalogues Intermediate-3 (Scheme-2)

Compounds of interest Intermediate-3 can be prepared according to thegeneral synthesis method shown in Scheme 2.

Compound XI can be obtained by the deprotection of Intermediate-2. Thereaction is typically performed in DCM with TFA at rt for 2 hours.

Compound XII can be obtained by coupling reaction from XI with ammonia.The reaction is typically performed in DCM with HATU and ammonia ofdioxane solution at rt for 1 hour.

Cyano compound Intermediate-3 can be obtained by dehydrate reaction fromcompound XII. The reaction is typically performed in 1,2-dichloroethanewith thionyl chloride or trifluoroacetic anhydride under refluxing for 1hour.

General synthetic scheme for 4-methyl-5-ester orcyano-6-aminoalkyl-dihydropyrimidine based analogues Ia (Scheme 3)

Compounds of interest Ia can be prepared according to the generalsynthesis method shown in Scheme 3.

The Boc-protected compound XIII can be obtained by treatment of esterIntermediated or cyano Intermediate-3 with di-tert-butyldicarbonate andDMAP as base in an inert organic solvent such as DCM, typically at rtfor 24 hours.

The compound XIV can be obtained by the bromination of compound XIII.The reaction is typically performed in tetrachloromethane with NBS andAIBN as catalyst at 80° C. for 2 hours.

The amino substituted intermediate XVI can be obtained throughsubstitution reaction of compound XIV with XV. The reaction can becarried out with a suitable organic base such asN,N-diisopropylethylamine, inorganic base such as NaH, Na₂CO₃, or t-BuOKin an inert organic solvent such as DCM, THF or DMF at rt or 50° C. for1-10 hours.

Compound Ia can be obtained from the deprotection of XVI treated withTFA in DCM or HCl in MeOH as deprotective agent at rt.

General synthetic scheme for 4-methyl-5-ester orcyano-6-alkoxymethyl-dihydropyrimidine based analogue Ib (Scheme 4)

Compound of interest Ib can be prepared according to the generalsynthesis method shown in Scheme 4.

Compound XVIII can be obtained by substitution reaction of compound XIVwith alcohol XVII. The reaction is typically performed by adding NaH tothe solution of alcohol XVII in anhydrous THF at it, then bromide XIV isadded into the flask and the mixture is stirred at rt for 3 hours.

Compound Ib can be obtained by treating XVIII with TFA in DCM or HCl inMeOH at rt.

This invention also relates to a process for the preparation of acompound of formula I comprising the reaction of

(a) a Compound of Formula (A)

in the presence of an acid;wherein R¹ to R⁵, M and X are defined above unless otherwise indicated.In step (a), the acid can be for example TFA or HCl.

Pharmaceutical Compositions and Administration

The invention also relates to a compound of formula I for use astherapeutically active substance.

A compound of formula (I) when manufactured according to the aboveprocess is also an object of the invention.

Another embodiment provides pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments. In oneexample, compounds of formula I may be formulated by mixing at ambienttemperature at the appropriate pH, and at the desired degree of purity,with physiologically acceptable carriers, i.e., carriers that arenon-toxic to recipients at the dosages and concentrations employed intoa galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, butpreferably ranges anywhere from about 3 to about 8. In one example, acompound of formula I is formulated in an acetate buffer, at pH 5. Inanother embodiment, the compounds of formula I are sterile. The compoundmay be stored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularhuman being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The “effective amount” of the compoundto be administered will be governed by such considerations, and is theminimum amount necessary to the suppression of serum HBV DNA levels, orHBeAg seroconversion to HBeAb, or HBsAg loss, or normalization ofalanine aminotransferase levels and improvement in liver histology. Forexample, such amount may be below the amount that is toxic to normalcells, or the human as a whole.

In one example, the pharmaceutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 0.1 to about1000 mg of the compound of the invention.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

An example of a suitable oral dosage form is a tablet containing about0.1 mg to 1000 mg of the compound of the invention compounded with about90 mg to 30 mg anhydrous lactose, about 5 mg to 40 mg sodiumcroscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, andabout 1 mg to 10 mg magnesium stearate. The powdered ingredients arefirst mixed together and then mixed with a solution of the PVP. Theresulting composition can be dried, granulated, mixed with the magnesiumstearate and compressed to tablet form using conventional equipment. Anexample of an aerosol formulation can be prepared by dissolving thecompound, for example 5 mg to 400 mg, of the invention in a suitablebuffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. asalt such sodium chloride, if desired. The solution may be filtered,e.g., using a 0.2 micron filter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodimentincludes a pharmaceutical composition comprising a compound of FormulaI, or a stereoisomer or pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or excipient.

Indications and Methods of Treatment

The compounds of the invention can inhibit HBV's de novo DNA synthesisand reduce HBV DNA levels. Accordingly, the compounds of the inventionare useful for the treatment or prophylaxis of HBV infection.

The invention relates to the use of a compound of formula I for thetreatment or prophylaxis of HBV infection.

The use of a compound of formula I for the preparation of medicamentsuseful in the treatment or prophylaxis diseases that are related to HBVinfection is an object of the invention.

The invention relates in particular to the use of a compound of formulaI for the preparation of a medicament for the treatment or prophylaxisof HBV infection.

Another embodiment includes a method of treating or prophylaxising HBVinfection in a human in need of such treatment, wherein the methodcomprises administering to said human a therapeutically effective amountof a compound of Formula I, a stereoisomer, tautomer, prodrug orpharmaceutically acceptable salt thereof.

Combination Therapy

The compounds of the invention can be used together with interferon,pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir,Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxisof HBV.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Abbreviations used herein are as follows:

-   AIBN: azobisisobutyronitrile-   Boc: tert-butoxycarbonyl-   t-BuOK: potassium tert-butoxide-   calc'd: calculated-   CC₅₀: cytotoxic concentration 50%-   CCl₄: tetrachloromethane-   CDCl₃: deuterated chloroform-   CCK-8: cell counting kit-8-   CDI: N,N′-Carbonyldiimidazole-   CMV: cytomegalovirus-   d: day-   DIPEA: N,N-diisopropylethylamine-   DCM: dichloromethylene-   DMAP: N,N′-dimethylaminopyridine-   DMF: dimethylformamide-   DMSO: dimethylsulfoxide-   DNA: deoxyribonucleic acid-   EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   EDTA: ethylenediaminetetraacetic acid-   exp: expected-   EtOAc: ethyl acetate-   FBS: fetal bovine serum-   g: gram-   EC₅₀: concentration required for 50% induction of acetylated tubulin-   FES: fetal bovine serum-   h: hour or hours-   HAP: heteroaryldihydropyrimidine-   HATU: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HBeAb: hepatitis B e antibody-   HBeAg: hepatitis B e antigen-   HBsAg: hepatitis B surface antigen-   HCl: hydrogen chloride-   HPLC: high performance liquid chromatography-   Hz: Hertz-   In(OTf)₃: indium (III) trifluoromethanesulfonate-   IPA: isopropanol-   KOH: potassium-   LC/MS: liquid chromatography mass spectrometer-   LiOH: lithium hydroxide-   LDA: lithium diisopropylamide-   MeOD-d4 or CD3OD:deuterated methanol-   MeOH: methanol-   mg: milligram-   MHz: megahertz-   min: minute or minutes-   mL: milliliter-   mM: milliliter-   NMP: 1-methyl-piperidin-2-one-   mmol: millimole-   NaCl: sodium chloride-   NaOH: sodium hydroxide-   NBS: N-bromosuccinimide-   NEt₃: triethylamine-   NMR: nuclear magnetic resonance-   PBS: Phosphate buffered saline-   prep-HPLC: preparative high performance liquid chromatography-   RP-HPLC: reverse phase high performance liquid chromatography-   rt: room temperature-   SDPK: single dose pharmacokinetics-   SFC: supercritical fluid chromatography-   SSC: saline-sodium citrate buffer-   TEA: triethylamine-   TFA: trifluoroacetic acid-   TFAA: trifluoroacetic acid anhydride-   THF: tetrahydrofuran-   μl: microliter-   μM: micromole

General Experimental Conditions

Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: i) Biotage SP1 system and theQuad 12/25 Cartridge module. ii) ISCO combi-flash chromatographyinstrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particlesize: 40-60 μM; ii) CAS registry NO: Silica Gel: 63231-67-4, particlesize: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang ChemicalCo., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC onreversed phase column using XBridge™ Prep-C₁₈ (5 μm, OBD™ 30×100 mm)column or SunFire™ Prep-C₁₈ (5 μM, OBD™ 30×100 mm) column. Waters AutoPpurification System (Column: XBridge™ Prep-C₁₈, 30×100 mm, SampleManager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solventsystem: acetonitrile and 0.1% ammonium hydroxide in water). For SFCchiral separation, intermediates were separated by chiral column (Daicelchiralpak IC, 5 μm, 30×250 mm) column using Mettler Toledo SFC-MultigramIII system, solvent system: 95% CO₂ and 5% IPA (0.5% TEA in IPA), backpressure 100 bar, detection UV@ 254 nm.

LC/MS spectra of compounds were obtained using a LC/MS (Waters™ Alliance2795-Micromass ZQ). LC/MS conditions were as follows (running time 6min):

Acidic condition: A: 0.1% formic acid in H₂O; B: 0.1% formic acid inacetonitrile;

Basic condition: A: 0.01% NH₃.H₂O in H₂O; B: acetonitrile;

Neutral condition: A: H₂O; B: acetonitrile.

Mass spectra (MS): generally only ions which indicate the parent massare reported, and unless otherwise stated the mass ion quoted is thepositive mass ion (M+H)⁺.

LC-MS/MS instrument on liver homogenate stability test: An Agilent 1290series LC system composited of a binary pump, a degasser, a CTCPALautosampler and a thermostatted column was applied. The Chromatographicseparation was achieved on a Chromolith Performance RP-18 endcapped(3×100 mm) at room temperature.

Mass spectrometric detection was performed on an Agilent 6530 Q-TOFinstrument in full scan mode with an AJS ESI interface in positiveionization mode. Data processing was performed with Agilent MassHunterWorkstation Data Acquisition B.04.00 and Agilent MassHunter WorkstationQualitative Analysis B.04.00.

The microwave assisted reactions were carried out in a Biotage InitiatorSixty microwave synthesizer.

NMR Spectra were obtained using Bruker Avance 400 MHz.

All reactions involving air-sensitive reagents were performed under anargon atmosphere. Reagents were used as received from commercialsuppliers without further purification unless otherwise noted.

The following examples were prepared by the general methods outlined inthe schemes above. They are intended to illustrate the meaning of thepresent invention but should by no means represent a limitation withinthe meaning of the present invention.

PREPARATIVE EXAMPLES Example 14-(4-Fluoro-phenyl)-6-(1-methoxycarbonyl-1-methyl-ethoxymethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared according to the general synthesismethods shown in Scheme 1 and Scheme 4. A detailed synthesis route isprovided as shown in Scheme 5.

To a stirred suspension of NH₄Cl in toluene (400 mL) was added Al(CH₃)₃solution (1.0 M, 56 mL) at 0° C. over 30 minutes. After the mixturesolution was stirred at rt for 30 minutes, the solution ofthiazole-2-carbonitrile (5.24 g, 47.6 mmol) in toluene (10 mL) was addedinto the flask. The reaction mixture was stirred at 80° C. for 16 hoursbefore cooling to rt and then the mixture was poured into a slurry ofsilica gel in DCM. After stirring for 20 minutes, the slurry wasfiltered and washed with MeOH three times and concentrated in vacuo toafford crude product of thiazole-2-carboxamidine XIX that was used innext step reaction without further purification. MS: calc'd (MH⁺) 128.2,exp (MH⁺) 128.1.

A mixture of 3-oxo-butyric acid methyl ester (5.0 g, 43.1 mmol),1-ethynyl-4-fluoro-benzene (5.0 g, 41.7 mmol) and In(OTf)₃ (400 mg, 0.71mmol) in o-xylene (20 ml) was heated to 120° C. for 1 to 2 h. Aftersolvent removal, the residue was purified by column chromatography(EtOAc/petroleum ether: 1/10) to afford XX as light yellowish oil (4.0g, yield: 40.8%).

To a mixture of thiazole-2-carboxamidine XIX (1.7 g, 10.5 mmol) andNaHCO₃ (2.5 g, 29.8 mmol) in NMP (10 mL) which was preheated to 120° C.was added dropwisely (E)-2-acetyl-3-(4-fluoro-phenyl)-but-2-enoic acidmethyl ester XX (2.4 g, 10.2 mmol) in NMP (10 mL) in about 1 h. Themixture was stirred at 120° C. for 0.5 h before reaction workup withEtOAc (200 mL) and water. The organic layer was dried and concentrated,and the residue was purified by column chromatography (EtOAc/petroleumether 1/4 to 1/2) to afford4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester XXI as yellow viscous oil (1.7 g, yield: 48.3%). MS:calc'd (MH⁺) 346, exp (MH⁺) 346. ¹H NMR (MeOD-d₄, 400 MHz) 7.93 (d, 1H,J=3.2 Hz), 7.72 (d, 1H, J=3.2 Hz), 7.51-7.47 (m, 2H), 7.04 (t, 2H, J=8.8Hz), 3.45 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H).

To a solution of XXI (1.0 g, 2.9 mmol) in DCM (20 mL) was added DMAP(0.15 g, 1.2 mmol) and Boc₂O (0.94 g, 4.3 mmol), and the mixture wasstirred overnight. The mixture was washed with water (15 mL) and brine(15 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated, and the residue was purified by column chromatography(EtOAc/petroleum ether from 1/4 to 1/3) to afford4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-4H-pyrimidine-1,5-dicarboxylicacid 1-tert-butyl ester 5-methyl ester XXII as yellow solid (0.91 g,yield: 70.5%).

A solution of XXII (0.90 g, 2.02 mmol) and NBS (0.54 g, 3.03 mmol) inCCl₄ (30 mL) was heated to 50° C., then AIBN (30 mg) was added toinitiate the reaction. The mixture was stirred for 2 h. The mixture waspurified by column chromatography (EtOAc/petroleum ether from 1/4 to1/3) to afford6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H-pyrimidine-1,5-dicarboxylicacid 1-tert-butyl ester 5-methyl ester XXIII as yellow solid (1.03 g,yield: 97.3%).

Sodium hydride (12 mg, 0.5 mmol) was added to a solution of2-hydroxy-2-methyl-propionic acid methyl ester (59 mg, 0.5 mmol) in THFat rt. Then the mixture was stirred at rt for 30 min. Compound XXIII(105 mg, 0.2 mmol) was added and stirred at rt overnight. Then themixture was partitioned between water and EtOAc. The organic phase wasdried, concentrated and used in the next step without furtherpurification.

The crude product XXIV from above step was dissolved in DCM and then TFAwas added. The mixture was stirred at rt for 2 hours. The solvent wasremoved and the residue was purified by prep-HPLC to afford Example 1 asyellow solid (40 mg, yield: 43% for 2 steps). MS: calc'd 462 (MH⁺), exp462 (MH⁺). ¹H NMR (MeOD-d₄, 400 MHz), 7.95 (d, 1H, J=3.2 Hz), 7.75 (d,1H, J=3.2 Hz), 7.49-7.45 (m, 2H), 7.04 (t, 2H, J=8.8 Hz), 4.71-4.62 (m,2H), 3.80 (s, 3H), 3.43 (s, 3H), 1.92 (s, 3H), 1.57 (s, 6H).

Example 26-(1-Carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1 in Scheme 5 byusing 3,3,3-trifluoro-2-hydroxy-propionic acid methyl ester instead of2-hydroxy-2-methyl-propionic acid methyl ester, the so-obtained methylester was hydrolyzed by LiOH as indicated in Scheme 3. MS: calc'd 488(MH⁺), exp 488 (MH⁺). ¹H NMR (MeOD-d₄, 400 MHz), 7.94 (d, 1H, J=2.8 Hz),7.93 (d, 1H, J=2.8 Hz), 7.53-7.49 (m, 2H), 7.07-7.03 (m, 2H), 4.85-4.78(m, 2H), 4.40-4.37 (m, 1H), 3.44 (s, 3H), 1.94 (s, 3H).

Example 36-{[(1-Carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared according to the synthesis method shownin Scheme 1 and Scheme 3. A detailed synthesis route is provided asshown in Scheme 6.

To a solution of6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H-pyrimidine-1,5-dicarboxylicacid 1-tert-butyl ester 5-methyl ester XXIII (1.00 g, 1.90 mmol) andpotassium carbonate in DMF was added1-methylamino-cyclopropanecarboxylic acid methyl ester (258 mg, 2.00mmol), the mixture was stirred at 40° C. for 3 hours and LC-MS indicatedthat the reaction was finished. The mixture was partitioned betweenwater and ethyl acetate. The organic phase was dried and concentrated toafford the crude product used in the next step without furtherpurification.

The crude product XXV from above step was dissolved in DCM and then TFAwas added. The mixture was stirred at rt for 2 hours. LC-MS indicatedthat the reaction was finished. The solvent was removed and the residuewas used in the next step without further purification.

The crude product XXVI from above step was dissolved in MeOH (5 mL) andLiOH in water (2 mL) was added to the mixture. The mixture was stirredat rt for 2 h and LC-MS indicated that the reaction was finished. Thesolvent was removed and the mixture was adjusted to pH (3˜5) withdiluted hydrochloric acid. The mixture was purified by prep-HPLC toafford Example 3 as yellow solid (0.63 g, yield for 3 steps: 73%). MS:calc'd 459 (MH⁺), exp 459 (MH⁺). ¹H NMR (MeOD-d₄, 400 MHz), 8.12 (d, 1H,J=3.2 Hz), 8.06 (d, 1H, J=3.2 Hz), 7.63-7.60 (m, 2H), 7.15 (t, 2H, J=8.8Hz), 4.30 (s, 2H), 3.51 (s, 3H), 2.79 (s, 3H), 2.10 (s, 3H), 1.52-1.51(m, 2H), 1.38-1.37 (m, 2H).

Example 44-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid

The title compound was prepared in analogy to Example 3 in Scheme 6 byusing morpholine-3-carboxylic acid methyl ester instead of1-methylamino-cyclopropanecarboxylic acid methyl ester. LC-MS: calc'd475 (MH⁺), exp 475 (MH⁺). ¹H NMR (MeOD-d₄, 400 MHz) δ 8.10 (d, 1H), 8.03(d, 1H), 7.64-7.61 (m, 2H), 7.15-7.12 (m, 2H), 4.32-4.31 (m, 2H),4.18-4.14 (m, 2H), 3.99-3.72 (m, 3H), 3.51-3.49 (m, 4H), 3.02 (m, 1H),2.11 (d, 3H).

Example 54-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 3 in Scheme 6 byusing morpholine-(S)-3-carboxylic acid methyl ester instead of1-methylamino-cyclopropanecarboxylic acid methyl ester.

Example 64-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid

The title compound was prepared by from the hydrolysis of Example 5 withLiOH in MeOH as shown in Scheme 6.

Example 7(S)-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid

The title compound was prepared according to the synthesis method shownin Scheme 1 and Scheme 3. A detailed synthesis route is provided asshown in Scheme 7.

The chiral intermediate compound XXVII was separated from XXI by SFC andthe absolute stereochemistry was determined by X-ray diffraction study(please see FIG. 7). The title compound was prepared in analogy toExample 3 in Scheme 6 by using morpholine-(S)-3-carboxylic acid methylester XXVIII instead of 1-methylamino-cyclopropanecarboxylic acid methylester in the replacement reaction.

Example 8(S)-4-[6-(4-Fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylicacid

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing morpholine-(R)-3-carboxylic acid methyl ester instead of1-methylamino-cyclopropanecarboxylic acid methyl ester.

Example 94-[6-(4-Fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylicacid

The title compound was prepared according to the methods shown in Scheme8.

5-Fluoro-pyridine-2-carbonitrile was used in the synthesis of CompoundXXIX in the same methods as shown in Scheme 5. Following similarprocedures to Scheme 5 and Scheme 6, XXIX was converted to Example 9 byusing morpholine-(R)-3-carboxylic acid methyl ester XXX in thereplacement reaction.

Example 104-[6-(4-Fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid

The title compound was prepared in analogy to Example 9 in Scheme 8 byusing morpholine-(S)-3-carboxylic acid methyl ester instead ofmorpholine-(R)-3-carboxylic acid methyl ester in the replacementreaction.

Example 116-(2-(S)-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 3 in Scheme 6 byusing 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl esterinstead of 1-methylamino-cyclopropanecarboxylic acid methyl ester.

Example 126-(2-(R)-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 3 in Scheme 6 byusing 4,4-difluoro-pyrrolidine-(R)-2-carboxylic acid methyl esterinstead of 1-methylamino-cyclopropanecarboxylic acid methyl ester.

Example 13(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl esterinstead of using morpholine-(S)-3-carboxylic acid methyl ester XXVIII inthe replacement reaction.

Example 14(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared according to the synthesis method shownin Scheme 1 and Scheme 3. A detailed synthesis route is provided asshown in Scheme 9.

A mixture of 3,4-difluoro-benzaldehyde (8.96 g, 63.1 mmol),3-oxo-butyric acid methyl ester (7.32 g, 63.1 mmol), piperidine (0.27 g,3.16 mmol) and acetic acid (0.19 g, 3.16 mmol) in anhydrous ethanol (200mL) was stirred for 12 hours at room temperature. After removal of thesolvent, the residue was purified by flash column chromatography(EtOAc:hexane=1:10) to afford the product of2-[1-(3,4-difluoro-phenyl)-meth-(Z)-ylidene]-3-oxo-butyric acid methylester XXXI as yellow solid (13.6 g). Yield: 90%. MS: calc'd (M⁺+H)241.0, exp (M⁺+H) 241.1.

A solution of methylithium (1.6 M in ether, 48.7 mL, 78 mmol) was addedto a suspension of copper(I) iodide (14.9 g, 78 mmol) in 200 mL ofanhydrous THF under argon at 0° C. and the mixture was stirred for 1hour at 0° C. A solution of XXXI (8.0 g, 31.2 mmol) in 50 mL ofanhydrous THF was added dropwisely into the mixture at −78° C. Afterstirring at −78° C. for 1 hour, the reaction mixture was quenched withsaturated ammonium chloride solution, extracted with EtOAc, washed withbrine and dried over anhydrous sodium sulfate. After removal of organicsolvent, the residue was purified by flash column chromatography(EtOAc:hexane=1:10) to afford 6.39 g of XXXII as oil. Yield: 80%. MS:calc'd (M⁺+H) 257.1.

NaH (60%, 1.10 g, 27.5 mmol) was added into a solution of XXXII (5.0 g,18.3 mmol) in anhydrous THF (100 mL) under argon. A solution ofphenylselenyl chloride (5.3 g, 27.5 mmol) in THF (20 mL) was added intothe flask at rt through syringe and the mixture was stirred at rt for 1h. 60 mL of pentene/ether mixture (v/v=1/1) and 30 mL of saturatedNaHCO₃ solution were added into the reaction mixture. The organic layerwas separated and washed with brine, and treated with H₂O₂ solution(30%, 4 mL) in DCM (50 mL) The mixture was stirred at rt (for 0.5˜2hours) and diluted with DCM (100 mL). The organic phase was separated,washed with saturated sodium bicarbonate, sodium sulfite, water andbrine in sequential and dried over anhydrous sodium sulfate. Afterremoval of organic solvent, the residue was purified by flash columnchromatography (EtOAc:hexane=1:10) to afford 3.97 g of XXXIII as yellowoil. MS: calc'd (M⁺+H) 255.1, exp (M⁺+H) 255.1

A mixture of XXXIII (2.54 g, 10 mmol), thiazole-2-carboxamidinehydrochloride XIX (1.6 g, 10 mmol) and sodium bicarbonate (1.68 g, 20mmol) in NMP (15 mL) was stirred for 3 hours at 120° C. After cooling,the mixture was separated between water and ethyl acetate. The organicphase was dried and concentrated. The residue was purified to afford theproduct of4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester XXXIV as yellow solid (2.00 g). Yield: 55%. MS: calc'd(M⁺+H) 363.1, exp (M⁺+H) 363.1.

The chiral intermediate XXXV was separated from XXXIV by SFC and theabsolute configuration was assigned through comparing its retention timeon SFC with that of the stereochemistry known compound XXVII.

The title compound Example 14 was prepared in analogy to Example 7 inScheme 7 from Compound XXXV.

Example 154-[(S)-6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid methyl ester

The title compound was prepared by the methods shown in Scheme 10 byusing XXXIV in the bromination and following replacement reactions,which were carried out in the same procedures as Scheme 5 and Scheme 6.

Example 164-[6-(3,4-Difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid

The title compound was obtained by hydrolysis of Example 15 with LiOH inMeOH.

Example 176-(4,4-Difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 9 in Scheme 8 byusing 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl esterinstead of morpholine-(R)-3-carboxylic acid methyl ester XXXVIII in thereplacement reaction.

Example 18(S)-6-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in the methods as shown in Scheme 11.

Compound XXXVI was obtained by SFC chiral separation of intermediateXXIX and the absolute configuration was assigned through comparing itsretention time on SFC with that of the stereochemistry known compoundXXVII. Example 9 was prepared from XXXVI by following the procedures inScheme 5 and Scheme 6, except that4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl ester XXXVII wasused in the replacement reaction.

Example 196-((S)-2-Carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in the methods as shown in Scheme 12 byusing 5-methyl-thiazole-2-carbonitrile in the preparation of ammidine.Compound XXXVIII was obtained by following the procedures in Scheme 5.And 4,4-difluoro-pyrrolidine-(S)-2-carboxylic acid methyl ester XXXVIIwas used in the preparation of Example 19, in methods similar to Scheme5 and Scheme 6.

Example 206-(2-Carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 3 in Scheme 6 byusing 4,4-difluoro-2-methyl-pyrrolidine-2-carboxylic acid methyl esterinstead of morpholine-3-carboxylic acid methyl ester.

Example 21(S)-1-[(S)-5-Cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid

The title compound was prepared according to the synthesis method shownin Scheme 2 and Scheme 3. A detailed synthesis route is provided asshown in Scheme 13.

Compound4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid tert-butyl ester XXXIX was prepared in analogy to XXXIV in Scheme 9by using 3-oxo-butyric acid tert-butyl ester and 4-fluoro-benzaldehydeinstead of 3-oxo-butyric acid methyl ester and 3,4-difluoro-benzaldehydein the condensation reaction.

To a solution of4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid tert-butyl ester XXXIX (1.0 g, 2.58 mmol) in DCM (15 mL) was addedTFA (2 mL), and the mixture was stirred for 3 hr. After that, thesolvent and excess TFA was removed in vacuum. The residue XL wasdissolved in DCM (15 mL), to which was added HATU (1.21 g, 3.70 mmol)and NH₃ in dioxane (10 mL, 0.5 M), and the mixture was stirredovernight. The mixture was diluted with DCM (50 mL), and washed withaqueous NaHCO₃ and brine. The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated to give 0.89 g of4-(4-fluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid amide as light yellow solid which was directly for next use withoutpurification.

The above crude intermediate (0.89 g) was dissolved in THF (10 mL), TFAA(3 mL) was added and the mixture was stirred for 3 hr. After removal ofTHF and excess TFAA, the residue was dissolved in MeOH (20 mL). To thesolution, K₂CO₃ (2.0 g, 14.5 mmol) was added, and the mixture wasstirred at rt for 3 hr. Then the mixture was filtered, the solid waswashed with EtOAc (10 mL×2). The combined filtrate was concentrated, theresidue was purified by column chromatography (EtOAc/petroleum ether 1/3to 1/2) to afford XLI as yellow solid (700 mg, totally yield: 87.0%).

The chiral intermediate XLII was separated from XLI by SFC.

The title compound Example 21 was prepared from XLII in analogy toExample 3 in Scheme 6.

Example 22(S)-4-[5-Cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid

The title compound was prepared according to the synthesis method shownin Scheme 2 and Scheme 3. A detailed synthesis route is provided asshown in Scheme 14.

Compound4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid tert-butyl ester XLIII was prepared in analogy to XXXIV in Scheme 9by using 3-oxo-butyric acid tert-butyl ester and3,4-difluorobenzaldehyde as starting material.

Compound4-(3,4-difluoro-phenyl)-4,6-dimethyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carbonitrileXLIV was prepared from tert-butyl ester XLIII in the same method as XLIin Scheme 13.

The title compound Example 22 was prepared in the same method as shownin Scheme 5 and Scheme 6 by using morpholine-(S)-3-carboxylic acidmethyl ester XXVIII in the replacement reaction.

Example 23(S)-1-[(S)-5-Cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid

The title compound was prepared according to the synthesis method shownin Scheme 2 and Scheme 3. A detailed synthesis route is provided asshown in Scheme 15.

Compound XLV was chiral separated from racemate XLIV by SFC and theabsolute configuration was assigned through comparing its retention timeon SFC with that of the stereochemistry known compound XXVII. The titlecompound was prepared in the same method as shown in Scheme 5 and Scheme6 by using XXXVII in the replacement reaction.

Example 24 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 4-ethynyl-1,2-difluoro-benzene instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 25 Preparation of(S)-6-(2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 5,5-difluoro-piperidine-2-carboxylic acid instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 26 Preparation of(S)-6-(2-carboxy-4,4-difluoro-piperidin-1-ylmethyl)4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 4,4-difluoro-piperidine-2-carboxylic acid instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 27 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 1-methyl-1H-imidazole-2-carbonitrile instead ofthiazole-2-carbonitrile.

Example 28 Preparation of(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 4-ethynyl-1,2-difluoro-benzene instead of1-ethynyl-4-fluoro-benzene.

Example 29 Preparation of(S)-4-[6-(3,4-difluoro-phenyl)-5-ethoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid

The title compound was prepared in analogy to Example 28 by using(S)-morpholine-3-carboxylic acid instead of(S)-4,4-difluoro-pyrrolidine-2-carboxylic acid.

Example 30 Preparation of(S)-4-[(S)-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-(1-methyl-1H-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid

The title compound was prepared in analogy to Example 27 by using(S)-morpholine-3-carboxylic acid instead of(S)-4,4-difluoro-pyrrolidine-2-carboxylic acid.

Example 31 Preparation of(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using4-methyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 32 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using4-methyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 33 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-(5-chloro-thiazol-2-yl)-4-(4-fluoro-phenyl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using5-chloro-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 34 Preparation of(S)-6-((2S,4R)-2-Carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (2S,4R)-4-fluoro-pyrrolidine-2-carboxylic acid instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 35 Preparation of6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-isoxazol-3-yl-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 11 by usingisoxazole-3-carbonitrile instead of thiazole-2-carbonitrile.

Example 36 Preparation of(R)-6-((S)-2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-2-methyl-pyrrolidine-2-carboxylic acid instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 37 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using5-methyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 38 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using5-fluoro-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 39 Preparation of(S)-6-((2S,4S)-2-carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (2S,4S)-4-fluoro-pyrrolidine-2-carboxylic acid instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 40 Preparation of6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-isoxazol-3-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 11 by using5-methyl-isoxazole-3-carbonitrile instead of thiazole-2-carbonitrile.

Example 41 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using3-fluoro-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 42 Preparation of(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using3-fluoro-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 43 Preparation of(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(4-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 13 by using4-fluoro-thiophene-2-carbonitrile instead of thiazole-2-carbonitrile.

Example 44 Preparation of(S)-6-{[carboxymethyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (2,2,2-trifluoro-ethylamino)-acetic acid instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 45 Preparation of(S)-6-((S)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid methyl esterinstead of (S)-morpholine-3-carboxylic acid methyl ester.

Example 46 Preparation of(S)-6-[(S)-2-(2-dimethylamino-ethoxycarbonyl)-4,4-difluoro-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid2-dimethylamino-ethyl ester instead of (S)-morpholine-3-carboxylic acidmethyl ester.

Example 47 Preparation of(S)-6-(2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 4,4-difluoro-pyrrolidine-2-carboxylic acid amide instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 48 Preparation of(S)-6-((S)-2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid amide instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 49 Preparation of(S)-6-((S)-2-dimethylcarbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid dimethylamideinstead of (S)-morpholine-3-carboxylic acid methyl ester.

Example 50 Preparation of6-((S)-4,4-difluoro-2-methylcarbamoyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid methylamide insteadof (S)-morpholine-3-carboxylic acid methyl ester.

Example 51 Preparation of(S)-6-((S)-4,4-difluoro-2-methanesulfonylaminocarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing N—((S)-4,4-difluoro-pyrrolidine-2-carbonyl)-methanesulfonamideinstead of (S)-morpholine-3-carboxylic acid methyl ester.

Example 52 Preparation of(S)-6-[(S)-4,4-difluoro-2-(thiazol-2-ylcarbamoye-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid thiazol-2-ylamideinstead of (S)-morpholine-3-carboxylic acid methyl ester.

Example 53 Preparation of4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl-morpholin-4-ylmethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing (R)-1-morpholin-3-yl-methanol instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 54 Preparation of(S)-6-[(S)-4,4-difluoro-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 2-((S)-4,4-difluoro-pyrrolidin-2-yl)-propan-2-ol instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 55 Preparation of(S)-6-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing ((S)-4,4-difluoro-pyrrolidin-2-yl)-methanol instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 56 Preparation of(S)-6-[4,4-difluoro-2-(3-hydroxy-propyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing ((S)-4,4-difluoro-pyrrolidin-2-yl)-propan-1-ol instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 57 Preparation of(S)-6-[(S)-4,4-difluoro-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 2-((S)-4,4-difluoro-pyrrolidin-2-yl)-5-methyl-[1,3,4]oxadiazoleinstead of (S)-morpholine-3-carboxylic acid methyl ester.

Example 58 Preparation of(S)-6-[(S)-4,4-difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 5-((S)-4,4-difluoro-pyrrolidin-2-yl)-1H-tetrazole instead of(S)-morpholine-3-carboxylic acid methyl ester.

Example 59 Preparation of(S)-6-[(S)-4,4-difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 7 in Scheme 7 byusing 5-((S)-4,4-difluoro-pyrrolidin-2-yl)-3-methyl-[1,2,4]oxadiazoleinstead of (S)-morpholine-3-carboxylic acid methyl ester.

BIOLOGICAL EXAMPLES Example 60 HBV Inhibition Assays (Biochemical Assay)

Cells and culture conditions: HepDE19 (Haitao Guo et al, Journal ofVirology, 81, November 2007, 12472-12484; Richeng Mao et al, Journal ofVirology, 85, January 2011, 1048-1057) cells were derived from HepG2(ATCC, American Type Culture Collection) cells through transfection withpTet-off plasmid (Clontech) that expresses the Tet-responsivetranscriptional activator and pTREHBVDE plasmid in which HBV pgRNAexpression is controlled by a CMV early promoter with atetracycline-responsive element. The transfected cells were selectedwith G418 (also known as Genticin, purchased from Invitrogen). Intetracycline-free medium, cells support high levels of HBV DNAreplication and HBV virus secretion. These cells were maintained inDulbecco's modified Eagle's medium (DMEM)-F12 medium (Invitrogen)supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100μg/ml streptomycin, 0.5 mg/ml of G418 and 1 μg/ml tetracycline.

Anti-HBV activity and cytotoxicity: HepDE19 cells were seeded into96-well plates (3×10⁴ cells/well) with tetracycline-free medium andincubated overnight at 37° C. The test or control compounds wereserially half-log diluted with medium and added into the plates (thefinal concentration of DMSO kept at 0.5% in each well). Five days aftercompound treatment, cells were washed with PBS and lysed with 50 mMTris-1 mM EDTA-0.2% CA-630 (pH 8.0) at 37° C. for 20 min. Aftercentrifugation to remove nuclei and other debris, the supernatant wastransferred into a new plate and incubated with 2M NaOH/20×SSC (3M NaCl,0.3M Sodium citrate, pH7.0) at rt for 30 min. Then the samples weretransferred to nylon membrane and neutralized withlM Tris (pH7.4)/2MNaCl. The presence of HBV DNA was detected by dot-blot with DIG-labeledHBV specific DNA probe and quantified by dot density. The compoundconcentrations that inhibited HBV DNA by 50% (EC₅₀) were determined (SeeTable 1).

To determine if the anti-HBV effect of compound is due to cytotoxicity,HepDE19 cells (5×10³ cells/well) were seeded into 96-well plates andcompounds were treated as described above. Five days after treatment,cell viability was measured by addition of 20 μl of CCK-8 reagent. Fourhours after incubation at 37° C., the absorbance at wavelengths of 450nm and 630 nm (OD₄₅₀ and OD₆₃₀) was recorded by a plate reader. The 50%cytotoxic concentration (CC₅₀) of each compounds were determinedaccordingly.

The compounds of the present invention were tested for their capacity toinhibit a HBV activity and activation as described herein. The Exampleswere tested in the above assay and found to have EC₅₀ of about 0.01 μMto about 50 μM. Particular compounds of formula I were found to haveEC₅₀ of about 0.1 μM to about 30 μM.

Results of HepDe19 EC₅₀ (μM) and CC₅₀ (μM) are given in Table 1.

Example A

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per Tablet

Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc  25 mg Hydroxypropylmethylcellulose  20 mg 425 mg

Example B

A compound of formula I can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per Capsule

Active ingredient 100.0 mg Corn starch  20.0 mg Lactose  95.0 mg Talc 4.5 mg Magnesium stearate  0.5 mg 220.0 mg

We claim:
 1. A compound of formula (I)

wherein: R¹ is C₁₋₂ alkoxycarbonyl or cyano; R² is phenyl, which issubstituted by halogen; R³ is thiazolyl, thienyl, imidazolyl, isoxazolylor pyridinyl; which is unsubstituted or substituted by halogen orC₁₋₆alkyl; X is oxygen or —NR⁷; R⁴ and R⁵ are independently selectedfrom hydrogen, C₁₋₆alkyl and trifluoroC₁₋₆alkyl; or R⁴ and R⁵, togetherwith the carbon atom to which they are attached, form a 3 to 7 memberedcycloalkyl; or when X is —NR⁷, one of R⁴ and R⁵ is hydrogen orC₁₋₆alkyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms towhich R⁴ or R⁵ and R⁷ are attached form a pyrrolidinyl, morpholinyl orpiperidinyl ring, which pyrrolidinyl, morpholinyl or piperidinyl ring isunsubstituted or substituted by fluoro; M is C₁₋₆ alkoxycarbonyl,carboxy, di-C₁₋₆alkylaminoC₂₋₆alkoxycarbonyl, aminocarbonyl,C₁₋₆alkylaminocarbonyl, di-C₁₋₆alkylaminocarbonyl,C₁₋₆alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,hydroxy-C_(y)H_(2y)—,

R⁷ is C₁₋₆alkyl or trifluoroC₁₋₆alkyl; y is 1-6; or pharmaceuticallyacceptable salts, or tautomerism isomers thereof.
 2. A compoundaccording to claim 1, wherein, R¹ is C₁₋₂alkoxycarbonyl or cyano; R² isphenyl, which is once or twice substituted by halogen; R³ is (i)2-thiazolyl which is unsubstituted or once substituted by C₁₋₆alkyl orhalogen, (ii) 2-thienyl, (iii) 2-pyridinyl, which 2-thienyl or2-pyridinyl are once substituted by halogen, (iv) 2-imidazolylsubstituted by one C₁₋₆alkyl; or (v) 3-isoxazolyl which is unsubstitutedor substituted by one C₁₋₆alkyl; X is oxygen or —NR⁷; R⁴ and R⁵ areindependently selected from hydrogen, C₁₋₆alkyl and trifluoroC₁₋₆alkyl;or R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3 to 7 membered cycloalkyl ring; or when X is —NR⁷, one of R⁴ andR⁵ is hydrogen or C₁₋₆alkyl, and the other of R⁴ and R⁵ along with R⁷and the atoms to which R⁴ or R⁵ and R⁷ are attached form a morpholinyl,pyrrolidinyl or piperidinyl each substituted by fluoro; M isC₁₋₆alkoxycarbonyl, carboxy, diC₁₋₆alkylamino-C₂₋₆alkoxycarbonyl,aminocarbonyl, C₁₋₆alkylaminocarbonyl, diC₁₋₆alkylaminocarbonyl,C₁₋₆alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,hydroxy-C_(y)H_(2y)—,

R⁷ is C₁₋₆alkyl or trifluoroC₁₋₆alkyl; y is 1-6; or pharmaceuticallyacceptable salts, or tautomerism isomers thereof.
 3. A compoundaccording to claim 2, wherein R² is phenyl substituted by one or twofluorine atoms; R³ is

R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl; or R⁴ and R⁵ together with the carbon atom to whichthey are attached are cyclopropyl; or when X is —NR⁷, one of R⁴ and R⁵is hydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and theatoms to which R⁴ or R⁵ and R⁷ are attached form:

M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl,aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl,methylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxymethyl,hydroxypropyl, —C(Me)₂OH,

R⁷ is methyl or trifluoroethyl; or pharmaceutically acceptable salts, ortautomerism isomers thereof.
 4. A compound according to claim 1 wherein.R¹ is C₁₋₂alkoxycarbonyl; R² is phenyl substituted by one halogen; R³ isthiazol-2-yl; X is oxygen; R⁴ and R⁵ are independently selected fromhydrogen, C₁₋₆alkyl and trifluoroC₁₋₆alkyl; M is C₁₋₆alkoxycarbonyl orcarboxy.
 5. A compound according to any one of claim 4, wherein; R¹ ismethoxycarbonyl; R² is 4-fluorophenyl; R³ is thiazol-2-yl; X is oxygen;R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl; M is methoxycarbonyl or carboxy.
 6. A compoundaccording to claim 1 wherein; R¹ is C₁₋₂alkoxycarbonyl; R² is phenylsubstituted by one halogen; R³ is 2-thiazolyl; X is —N(C₁₋₆alkyl) or—N(trifluoroC₁₋₆alkyl); R⁴ is hydrogen; R⁵ is hydrogen; or R⁴ and R⁵,together with the carbon atom to which they are attached, form a 3 to 7membered cycloalkyl; M is carboxy.
 7. A compound according to any one ofclaim 6, wherein: R¹ is methoxycarbonyl; R² is 4-fluorophenyl; R³ isthiazol-2-yl; X is —NCH₃ or —NCH₂CF₃; R⁴ is hydrogen; R⁵ is hydrogen; orR⁴ and R⁵, together with the carbon atom to which they are attached,form cyclopropyl; M is carboxy.
 8. A compound according to claim 1wherein R¹ is C₁₋₂alkoxycarbonyl or cyano; R² is phenyl substituted byone kor two halogen; R³ isthiazol-2-yl; 2-pyridin-2-yl substituted byone halogen; or imidazol-2-yl substituted by one C₁₋₆alkyl; X is —NR⁷;one of R⁴ and R⁵ is hydrogen, and the other of R⁴ and R⁵ along with R⁷and the atoms to which R⁴ or R⁵ and R⁷ are attached form a morpholinyl;M is C₁₋₆alkoxycarbonyl, carboxy or hydroxy-C_(y)H_(2y)—; y is 1-6.
 9. Acompound according to any one of claim 8, wherein R¹ is methoxycarbonyl,ethoxycarbonyl or cyano; R² is 4-fluorophenyl or 3,4-difluorophenyl; R³is thiazol-2-yl, 5-fluoro-pyridin-2-yl or 1-methyl-imidiazolid-2-yl; oneof R⁴ and R⁵ is hydrogen, and the other of R⁴ and R⁵ along with R⁷ andthe atoms to which R⁴ or R⁵ and R⁷ are attached form:

M is methoxycarbonyl, carboxy or hydroxymethyl-.
 10. A compoundaccording to claim 1 or 2, wherein R¹ is C₁₋₂alkoxycarbonyl or cyano; R²is phenyl substituted by one or two halogen; R³ is thiazol-2-yloptionally substituted by one C₁₋₆alkyl or one halogen; thien-2-yl or-pyridin-2-yl said thien-2-yl or -pyridin-2-yl substituted by onehalogen; -imidazol-2-yl, which substituted by one C₁₋₆alkyl; orisoxazol-3-yl optionally substituted by one C₁₋₆alkyl; X is —NR⁷; one ofR⁴ and R⁵ is hydrogen or C₁₋₆alkyl, and the other of R⁴ and R⁵ alongwith R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form apyrrolidinyl or piperidinyl substituted by fluoro; M isC₁₋₆alkoxycarbonyl, carboxy, di-C₁₋₆alkylaminoC₂₋₆alkoxycarbonyl,aminocarbonyl, C₁₋₆alkylaminocarbonyl, di-C₁₋₆alkylaminocarbonyl,C₁₋₆alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl,hydroxy-C_(y)H_(2y)—,

y is 1-6.
 11. A compound according to any one of claim 1, 2, 3 or 10,wherein R¹ is methoxycarbonyl, ethoxycarbonyl or cyano; R² is4-fluorophenyl or 3,4-difluorophenyl; R³ is

X is —NR⁷; one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴and R⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attachedform:

M is methoxycarbonyl, carboxy, dimethylaminoethoxycarbonyl,aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl,methylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxymethyl,hydroxypropyl, —C(Me)₂OH,


12. A compound according to claim 1 of formula (I′)

wherein, R¹ is C₁₋₂alkoxycarbonyl or cyano; R² is phenyl, which issubstituted by halogen; R³ is 2-thiazolyl which is unsubstituted orsubstituted by C₁₋₆alkyl or 2-pyridinyl, which is substituted byhalogen; X is oxygen or —NR⁷; R⁴ and R⁵ are independently selected fromhydrogen, C₁₋₆alkyl and trifluoroC₁₋₆alkyl; or R⁴ and R⁵, together withthe carbon atom to which they are attached, form a 3 to 7 memberedcycloalkyl; or when X is —NR⁷, one of R⁴ and R⁵ is hydrogen orC₁₋₆alkyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms towhich R⁴ or R⁵ and R⁷ are attached form a morpholinyl; or pyrrolidinylsubstituted by fluoro; R⁶ is hydrogen or C₁₋₆alkyl; R⁷ is C₁₋₆alkyl; orpharmaceutically acceptable salts, or tautomerism isomers thereof.
 13. Acompound according to claim 12, wherein R¹ is methoxycarbonyl or cyano;R² is phenyl substituted once or twice by fluoro; R³ is thiazol-2-yl,5-methyl-thiazol-2-yl or 5-fluoro-pyridin-2-yl; or; X is oxygen or —NR⁷;R⁴ and R⁵ are independently selected from hydrogen, methyl andtrifluoromethyl; or R⁴ and R⁵ together with the carbon atom to whichthey are attached form cyclopropyl; or when X is —NR⁷, one of R⁴ and R⁵is hydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and theatoms to which R⁴ or R⁵ and R⁷ are attached form:

R⁶ is hydrogen or methyl; R⁷ is methyl; or pharmaceutically acceptablesalts, or tautomerism isomers thereof.
 14. A compound according to claim12, wherein R¹ is C₁₋₂alkoxycarbonyl or cyano; R² is phenyl which issubstituted by halogen; R³ is thiazol-2-yl or pyridin-2-yl, which issubstituted by halogen; X is —NR⁷; one of R⁴ and R⁵ is hydrogen orC₁₋₆alkyl, and the other of R⁴ and R⁵ along with R⁷ and the atoms towhich R⁴ or R⁵ and R⁷ are attached form a morpholinyl; R⁶ is hydrogen orC₁₋₆alkyl.
 15. A compound according to any one of claim 14, wherein R¹is methoxycarbonyl or cyano; R² is 4-fluorophenyl or 3,4-difluorophenyl;R³ is thiazol-2-yl or 5-fluoro-pyridin-2-yl; one of R⁴ and R⁵ ishydrogen or methyl, and the other of R⁴ and R⁵ along with R⁷ and theatoms to which R⁴ or R⁵ and R⁷ are attached formform

R⁶ is hydrogen or methyl.
 16. A compound according to claim 12, whereinR¹ is C₁₋₂alkoxycarbonyl or cyano; R² is phenyl which is substituted byhalogen; R³ is 2-thiazolyl optionally substituted by C₁₋₆alkyl or2-pyridinylsaid pyridinyl substituted by halogen; X is —NR⁷; one of R⁴and R⁵ is hydrogen or C₁₋₆alkyl, and the other and the other of R⁴ andR⁵ along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attachedform a pyrrolidinyl substituted by fluoro; R⁶ is hydrogen or C₁₋₆alkyl.17. A compound according to any one of claims 16, wherein R¹ ismethoxycarbonyl or cyano; R² is 4-fluorophenyl or 3,4-difluorophenyl; R³is thiazol-2-yl, 5-methyl-thiazol-2-yl or 5-fluoro-pyridin-2-yl; X is—NR⁷; one of R⁴ and R⁵ is hydrogen or methyl, and the other of R⁴ and R⁵along with R⁷ and the atoms to which R⁴ or R⁵ and R⁷ are attached form

R⁶ is hydrogen or methyl.
 18. A compound according to any one of claims1 selected from4-(4-fluoro-phenyl)-6-(1-methoxycarbonyl-1-methyl-ethoxymethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-(1-carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-{[(1-carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid;4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid methyl ester;4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid;(S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid;(S)-4-[6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylicacid;4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(R)-3-carboxylicacid;4-[6-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-5-methoxycarbonyl-6-methyl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-(S)-3-carboxylicacid;6-(2-(S)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-(2-(R)-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;4-[(S)-6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid methyl ester;4-[6-(3,4-difluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid;6-(4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-(2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-pyridin-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-(2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-1-[(S)-5-cyano-6-(4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid;(S)-4-[5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid;(S)-1-[(S)-5-cyano-6-(3,4-difluoro-phenyl)-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester;(S)-6-(2-carboxy-5,5-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-(2-carboxy-4,4-difluoro-piperidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(1-methyl-1H-imidazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(3,4-difluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester;(S)-4-[6-(3,4-difluoro-phenyl)-5-ethoxycarbonyl-6-methyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid;(S)-4-[(S)-6-(4-fluoro-phenyl)-5-methoxycarbonyl-6-methyl-2-(1-methyl-1H-imidazol-2-yl)-3,6-dihydro-pyrimidin-4-ylmethyl]-morpholine-3-carboxylicacid;(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(4-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-2-(5-chloro-thiazol-2-yl)-4-(4-fluoro-phenyl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((2S,4R)-2-carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-isoxazol-3-yl-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-((S)-2-carboxy-4,4-difluoro-2-methyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(5-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((2S,4S)-2-carboxy-4-fluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-(5-methyl-isoxazol-3-yl)-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(3-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-2-(4-fluoro-thiophen-2-yl)-4-methyl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-{[carboxymethyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-4,4-difluoro-2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-[(S)-2-(2-dimethylamino-ethoxycarbonyl)-4,4-difluoro-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-(2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-carbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-2-dimethylcarbamoyl-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;6-((S)-4,4-difluoro-2-methylcarbamoyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-4,4-difluoro-2-methanesulfonylaminocarbonyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-[(S)-4,4-difluoro-2-(thiazol-2-ylcarbamoyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;4-(4-fluoro-phenyl)-6-((R)-3-hydroxymethyl-morpholin-4-ylmethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-[(S)-4,4-difluoro-2-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-((S)-4,4-difluoro-2-hydroxymethyl-pyrrolidin-1-ylmethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-[4,4-difluoro-2-(3-hydroxy-propyl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-[(S)-4,4-difluoro-2-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester;(S)-6-[(S)-4,4-difluoro-2-(1H-tetrazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester; and(S)-6-[(S)-4,4-difluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-ylmethyl]-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester.
 19. A process for the preparation of a compoundaccording to claim 1 comprising the reaction of (a) a compound offormula (A)

in the presence of an acid; wherein R¹ to R⁵, M and X are defined as inclaim
 1. 20. A compound according to any one of claim 1 for use astherapeutically active substance.
 21. A pharmaceutical compositioncomprising a compound in accordance with any one of claim 1 and at leastone carrier, diluent or excipient.
 22. The use of a compound accordingto any one of claim 1 for the treatment or prophylaxis of hepatitis Bvirus infection.
 23. The use of a compound according to any one of claim1 for the preparation of a medicament for the treatment or prophylaxisof hepatitis B virus infection.
 24. A compound according to any one ofclaim 1 for the treatment or prophylaxis of hepatitis B virus infection.25. A compound according to any one of claims 1 when manufacturedaccording to a process of claim
 19. 26. A method for the treatment orprophylaxis of hepatitis B virus infection, which method comprisesadministering an effective amount of a compound as defined in any one ofclaim 1.